Drug Combinations and Uses in Treating a Coughing Condition

ABSTRACT

The present specification discloses compositions comprising a plurality of therapeutic compound having antitussive activity and methods and uses for treating a coughing condition with such compositions.

This continuation-in-part application claims priority pursuant to 35U.S.C. § 120 to U.S. patent application Ser. No. 15/144,800, filed May2, 2016, a continuation application of U.S. patent application Ser. No.14/488,215, filed Sep. 16, 2014, a continuation-in-part application ofU.S. patent application Ser. No. 13/446,217, filed Apr. 13, 2012, acontinuation-in-part application of International patent ApplicationPCT/GB2011/051610, filed Aug. 25, 2011, which claims priority to GBProvisional 1014391.5, filed Aug. 27, 2010; International patentApplication PCT/GB2010/052085, filed Dec. 14, 2010, which claimspriority to GB Provisional 0921805.8, filed Dec. 14, 2009; Internationalpatent Application PCT/GB2010/052086, filed Dec. 14, 2010, which claimspriority to GB Provisional 0921803.3, filed Dec. 14, 2009; Internationalpatent Application PCT/GB2010/051895, filed Nov. 12, 2010, which claimspriority to GB Provisional 0919889.6 filed Nov. 13, 2009; Internationalpatent Application PCT/GB2010/051896, filed Nov. 12, 2010, which claimspriority to GB Provisional 0919893.8 filed Nov. 13, 2009; Internationalpatent Application PCT/GB2010/050997, filed Jun. 15, 2010, which claimspriority to GB Provisional 0910375.5, filed Jun. 16, 2009; and GBProvisional 1111485.7, filed Jul. 5, 2011, each of which is herebyincorporated by reference in its entirety.

A cough is a protective reflexive action that helps clear the largebreathing passages of the lungs from bodily secretions, irritants,foreign particles and microbes. A cough occurs when special cells alongthe air passages get irritated and trigger a chain of events, resultingin air being forced out of the lungs under high pressure. The coughreflex includes three phases: an inhalation, a forced exhalation againsta closed glottis, and a violent release of air from the lungs followingopening of the glottis, usually accompanied by a distinctive sound.Coughing can happen voluntarily as well as involuntarily.

Cough, although a common affliction, may have one or a combination ofcauses. For example, cough may be a result of a simple viral upperrespiratory infection, of short duration, lasting but a few weeks (acutecough). However, cough can be persistent, lasting for several weeks,months, or even years (chronic cough). Chronic cough may be caused bycontinuous mucus drainage down the throat, asthma, gastroesophagealreflux, a variety of pulmonary disorders including chronic bronchitisand lung tumors, pollutants, choking, cardiovascular disorders, and evenas a side effect of certain medications such as Angiotensin-ConvertingEnzyme (ACE) inhibitors. In some cases, coughing serves as a protectivemechanism by preventing aspiration of foreign material into the lungsor, as with infectious processes, expulsion of unwanted mucus andpathogens from the airway. However, in many cases of chronic cough, themechanism serves no useful purpose and may dramatically affect one'sentire lifestyle causing sleeplessness, exhaustion, annoyance, selfconsciousness, and social limitation. Physical consequences may behoarseness, incontinence of urine or stool, perspiration, and chest wallpain. Therefore, in those situations where cough serves no usefulpurpose, the benefit of a pharmaceutical composition and/or therapeuticcompound to suppress cough, termed antitussives, are highly desirable.

The complications of coughing can be classified as either acute orchronic. Acute complications include cough syncope (fainting spells dueto decreased blood flow to the brain when coughs are prolonged andforceful), insomnia, cough-induced vomiting, rupture of blebs causingspontaneous pneumothorax (although this still remains to be proven),subconjunctival hemorrhage or “red eye”, coughing defecation and inwomen with a prolapsed uterus, cough urination. Chronic complicationsare common and include abdominal or pelvic hernias, fatigue fractures oflower ribs and costochondritis.

Even though cough medicines are a common an over-the-counter remedy forindividuals seeking outpatient medical attention, their effectiveness asa treatment for a cough is doubtful. In 2006, the American College ofChest Physicians issued guidelines stating that “most over the countercough medications are ineffective”, and several research reports seem toconfirm this conclusion. For example, the non-opiate antitussive drugDextromethorphan is marketed as a cough therapy. However, its efficacyand suitability as a treatment for cough is questionable, since itsapparent success as a clinical treatment was attributed to a placeboeffect; Dextromethorphan itself had no efficacy in treating cough.(Ramsey et al., Br. J. Clin. Pharmacol.) Similarly, the decongestantpseudoephedrine has been to shown to have very limited efficacy in thecitric acid induced cough model in guinea-pigs (Minamizawa et. al., JPharmacol. Sci. 102(1); 136-142, 2006) and most of the literature failsto demonstrate that pseudoephedrine has an antitussive effect. In fact,although a number of papers describe effects of pseudoephedrine on“cough and cold” (which has little meaning in the medical field), nonedescribes or even examines direct antitussive effect. Lastly, a reviewarticle reports that presumptions about efficacy of the antihistaminediphenhydramine against cough in humans are not univocally substantiatedin literature. (Bjornsdottir et al., Pharma. World Sci. 29(6): 577-583,2007). In other words, there is no strong evidence that antihistamineshave any efficacy in cough.

Thus, there is a still exists a need for the development ofpharmaceutical compositions and/or therapeutic compounds having anantitussive activity.

SUMMARY

Aspects of the present specification disclose compositions comprising aplurality of therapeutic compounds having antitusive activity.Therapeutic compounds include, without limitation, a methylxanthine, anon-opiate antitussive agent, an opiate antitussive agent, adecongestant, an expectorant, a mucolytic agent, an anti-histamine, anon-steroidal anti-inflammatory drug (NSAID), a neuropathic pain agent,a terpene, an ACE inhibitor, an angiotensin II receptor antagonist orany combination thereof. The composition disclosed herein may reduce anunwanted side and/or reduce a symptom associated with a coughingcondition. The composition disclosed herein may suppress a vagal nervefunction associated with a cough, suppress a central nerve functionassociated with a cough, and/or suppress a peripheral nerve functionassociated with a cough.

Aspects of the present specification also disclose compositionscomprising a methylxanthine and a plurality of additional therapeuticcompounds having antitusive activity. Methylxanthines include, withoutlimitation, Aminophylline, Caffeine, IBMX, Paraxanthine, Pentoxifylline,Theobromine, Theophylline, Xanthine, or any combination thereof.Additional therapeutic compounds include, without limitation, anon-opiate antitussive agent, an opiate antitussive agent, adecongestant, an expectorant, a mucolytic agent, an anti-histamine, anon-steroidal anti-inflammatory drug (NSAID), a neuropathic pain agent,a terpene, an ACE inhibitor, an angiotensin II receptor antagonist orany combination thereof. The composition disclosed herein may reduce anunwanted side and/or reduce a symptom associated with a coughingcondition. The composition disclosed herein may suppress a vagal nervefunction associated with a cough, suppress a central nerve functionassociated with a cough, and/or suppress a peripheral nerve functionassociated with a cough.

Aspects of the present specification also disclose methods of treating acoughing condition in an individual. The disclosed methods comprisingthe step of administering a pharmaceutical composition disclosed hereinto an individual, wherein administration reduces a symptom associatedwith the coughing condition. The coughing condition may be an acutecoughing condition, a subacute coughing condition, or a chronic coughingcondition. The coughing condition may be a non-productive coughingcondition or a productive coughing condition. The coughing condition maybe a cough associated with a disease or disorder. Administration of apharmaceutical composition may also reduce an unwanted side in theindividual.

Aspects of the present specification disclose uses of the disclosedcompositions and/or therapeutic compounds in the manufacture of amedicament for the treatment of a coughing condition.

Aspects of the present specification disclose uses of the disclosedcompositions and/or therapeutic compounds in the treatment of a coughingcondition.

DESCRIPTION

The present specification discloses combinations of various therapeuticcompounds that when combined produce synergistic effects in reducing asymptom associated with a coughing condition. Consequently, aconsiderably reduced dose of both therapeutic compounds can be given foran equivalent effect for each individual therapeutic compound, therebyreducing side-effects and drug burden.

In addition, the present specification discloses that administration ofthe disclosed combinations of various therapeutic compounds byinhalation, a therapeutically effect is observed at one-third the doseadministered orally. Via the inhaled route, therapeutic compoundsdisclosed herein are surprisingly potent and do not follow the oralPK/PD relationship, revealing that the disclosed combinations of varioustherapeutic compounds have a substantially local effect in the lung.Consequently, via the inhaled route, less drug is given for anequivalent oral effect, so reducing side-effects and drug burden.

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. As used herein, the term “pharmaceutical composition” issynonymous with “pharmaceutically acceptable composition” and refers toa therapeutically effective concentration of an active ingredient, suchas, e.g., any of the therapeutic compounds disclosed herein. As usedherein, the term “pharmaceutically acceptable” refers to any molecularentity or composition that does not produce an adverse, allergic orother untoward or unwanted reaction when administered to an individual.A pharmaceutical composition disclosed herein is useful for medical andveterinary applications. A pharmaceutical composition may beadministered to an individual alone, or in combination with othersupplementary active ingredients, agents, drugs or hormones.

A pharmaceutical composition disclosed herein may comprise one or moretherapeutic compounds disclosed herein. In one embodiment,pharmaceutical composition disclosed herein may comprise only a single atherapeutic compound having antitussive activity. In another embodiment,pharmaceutical composition disclosed herein may comprise a plurality oftherapeutic compounds having antitussive activity. In aspects of thisembodiment, a pharmaceutical composition disclosed herein comprises atleast one therapeutic compound having antitussive activity, at least twotherapeutic compounds having antitussive activity, at least threetherapeutic compounds having antitussive activity, or at least fourtherapeutic compounds having antitussive activity. In other aspects ofthis embodiment, a pharmaceutical composition disclosed herein comprisesat most two therapeutic compounds having antitussive activity, at mostthree therapeutic compounds having antitussive activity, or at most fourtherapeutic compounds having antitussive activity. In yet other aspectsof this embodiment, a pharmaceutical composition disclosed hereincomprises one to three therapeutic compounds having antitussiveactivity, two to four therapeutic compounds having antitussive activity,two to five therapeutic compounds having antitussive activity, three tofive therapeutic compounds having antitussive activity, or two to threetherapeutic compounds having antitussive activity. In aspects of thisembodiment, a therapeutic compound having antitussive activity includes,without limitation, a methylxanthine, a non-opiate antitussive agent, anopiate antitussive agent, a decongestant, an expectorant, a mucolyticagent, an anti-histamine, a non-steroidal anti-inflammatory drug(NSAID), a neuropathic pain agent, a terpene, an ACE inhibitor, and/oran angiotensin II receptor antagonist.

In another embodiment, a pharmaceutical composition disclosed hereincomprises a methylxanthine and a single additional therapeutic compoundhaving antitussive activity. In another embodiment, a pharmaceuticalcomposition disclosed herein comprises a methylxanthine and a pluralityof additional therapeutic compound having antitussive activity. Inaspects of this embodiment, a pharmaceutical composition disclosedherein comprises a methylxanthine and at least one additionaltherapeutic compound having antitussive activity at least two additionaltherapeutic compounds having antitussive activity, at least threeadditional therapeutic compounds having antitussive activity, at leastfour additional therapeutic compounds having antitussive activity. Inother aspects of this embodiment, a pharmaceutical composition disclosedherein comprises a methylxanthine and at most one additional therapeuticcompound having antitussive activity, at most two additional therapeuticcompounds having antitussive activity, at most three additionaltherapeutic compounds having antitussive activity, at most fouradditional therapeutic compounds having antitussive activity. In yetother aspects of this embodiment, a pharmaceutical composition disclosedherein comprises a methylxanthine and one to three additionaltherapeutic compounds having antitussive activity, two to fouradditional therapeutic compound having antitussive activity, two tothree additional therapeutic compounds having antitussive activity, twoto five additional therapeutic compound having antitussive activity, orthree to five additional therapeutic compound having antitussiveactivity. In aspects of this embodiment, an additional therapeuticcompound having antitussive activity includes, without limitation, anon-opiate antitussive agent, an opiate antitussive agent, adecongestant, an expectorant, a mucolytic agent, an anti-histamine, anon-steroidal anti-inflammatory drug (NSAID), a neuropathic pain agent,a terpene, an ACE inhibitor, and/or an angiotensin II receptorantagonist.

In another embodiment, a pharmaceutical composition disclosed hereincomprises a methylxanthine and a plurality of therapeutic compoundshaving antitussive activity disclosed herein, wherein the plurality oftherapeutic compounds does not include a non-opiate antitussive agentdisclosed herein. In an aspect of this embodiment, a pharmaceuticalcomposition disclosed herein comprises a methylxanthine and a pluralityof therapeutic compounds having antitussive activity, wherein theplurality of therapeutic compounds does not include Dextromethorphan.

In another embodiment, a pharmaceutical composition disclosed hereincomprises a methylxanthine and a plurality of therapeutic compoundshaving antitussive activity disclosed herein, wherein the plurality oftherapeutic compounds does not include an anti-histamine disclosedherein. In an aspect of this embodiment, a pharmaceutical compositiondisclosed herein comprises a methylxanthine and a plurality oftherapeutic compounds having antitussive activity, wherein the pluralityof therapeutic compounds does not include Azatadine,Bromodiphenhydramine, Brompheniramine, Carbinoxamine, Cetirizine,Chlorpheniramine, Clemestine, Dexchlorpheniramine, Dexbrompheniramine,Diphenhydramine, Doxylamine, Pyrilamine, Tripelennamine, or Tripolidine.

A pharmaceutical composition disclosed herein may reduce an unwantedside effect elicited by administration of one or more of the therapeuticcompounds contained in the pharmaceutical composition. Examples ofunwanted side effects, include, without limitation, sedation, cognitivefogging, dizziness, drowsiness, postural hypertension, coordinationproblems, weakness, tremors, respiratory depression, psychotropiceffects, sleep disturbances, unwanted waitfulness, CNS stimulation,weight gain, appetite change, change in sexual function, constipation,dry mouth, gut erosion, gastric ulcerations, renal inflammation,cardiovascular hypertension, cardiovascular stimulation, hyperchlimina,not going into public, chest pain, and/or stress incontinence.

In aspects of this embodiment, an unwanted side-effect associated with anon-opiate antitussive agent, includes, without limitation, sedation,psychotropic effect, hallucination, or any combination thereof. In otheraspects of this embodiment, an unwanted side-effect associated with anopiate antitussive agent includes, without limitation, sedation,constipation, respiratory depression, or any combination thereof. In yetother aspects of this embodiment, an unwanted side-effect associatedwith a decongestant includes, without limitation, unwanted waitfulness,CNS stimulation, cardiovascular stimulation, tachycardia, or anycombination thereof. In still other aspects of this embodiment, anunwanted side-effect associated with an antihistamine includes, withoutlimitation, sedation, dry mouth, a sensory-based side effect, ananti-muscarinic side effect, or any combination thereof.

In other aspects of this embodiment, an unwanted side-effect associatedwith a NSAID, includes, without limitation, gut erosion, gastriculcerations, renal inflammation, cardiovascular hypertension, or anycombination thereof. In yet other aspects of this embodiment, anunwanted side-effect associated with a neuropathic pain agent, includes,without limitation, cognitive fogging, dizziness, drowsiness,coordination problems, weakness, tremors, weight gain, appetite change,change in sexual function, sleep disturbance, or any combinationthereof. In still other aspects of this embodiment, an unwantedside-effect associated with an ACE inhibitor, includes, withoutlimitation, coughing, hyperchlimina, postural hypertension, dizziness,headache, drowsiness, weakness, or any combination thereof. In furtheraspects of this embodiment, an unwanted side-effect associated with anangiotension 2 receptor antagonist, includes, without limitation,coughing, hyperchlimina, postural hypertension, dizziness, headache,drowsiness, weakness, or any combination thereof.

Aspects of the present specification disclose, in part, a therapeuticcompound. A therapeutic compound is a compound that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. Any suitableform of a therapeutic compound may be chosen. A therapeutic compounddisclosed herein may be used in the form of a pharmaceuticallyacceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride.Additionally, therapeutic compound disclosed herein may be provided asracemates, or as individual enantiomers, including the R- orS-enantiomer. Thus, the therapeutic compound disclosed herein maycomprise a R-enantiomer only, a S-enantiomer only, or a combination ofboth a R-enantiomer and a S-enantiomer of a therapeutic compound. Atherapeutic compound disclosed herein may also be provided as prodrug oractive metabolite.

A therapeutic compound disclosed herein may have antitussive activity.As used herein, the term “antitussive activity” refers to the ability ofa therapeutic compound to reduce a symptom associated with a coughingcondition, including, without limitation, the frequency of a cough, theseverity of a cough, the volume or noise level of a cough, hoarseness,sore throat, breathing difficulty, respiratory congestion, wheezing,respiratory constriction, respiratory inflammation, muscle spasmsassociated with a cough, phlegm production, fainting, insomnia,vomiting, subconjunctival hemorrhage (red eye), cough defecation, coughurination, abdominal hernia, pelvic hernia, costochondritis, and lowerrib fractures.

In one embodiment, a therapeutic compound disclosed herein havingantitussive activity reduces a symptom associated with a coughingcondition. In aspects of this embodiment, a therapeutic compound havingantitussive activity reduces a symptom associated with a coughingcondition by, e.g., at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90% or at least 95%. In otheraspects of this embodiment, a therapeutic compound having antitussiveactivity reduces a symptom associated with a coughing condition by,e.g., about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about10% to about 90%, about 20% to about 90%, about 30% to about 90%, about40% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 10% to about 80%, about 20% to about 80%, about30% to about 80%, about 40% to about 80%, about 50% to about 80%, orabout 60% to about 80%, about 10% to about 70%, about 20% to about 70%,about 30% to about 70%, about 40% to about 70%, or about 50% to about70%.

In another embodiment, a therapeutic compound disclosed herein havingantitussive activity reduces the frequency of a cough or the number ofcoughs that incur over a given time period. In aspects of thisembodiment, a therapeutic compound having antitussive activity thefrequency of a cough by, e.g., at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90% or at least 95%. Inother aspects of this embodiment, a therapeutic compound havingantitussive activity reduces the frequency of a cough by, e.g., about10% to about 100%, about 20% to about 100%, about 30% to about 100%,about 40% to about 100%, about 50% to about 100%, about 60% to about100%, about 70% to about 100%, about 80% to about 100%, about 10% toabout 90%, about 20% to about 90%, about 30% to about 90%, about 40% toabout 90%, about 50% to about 90%, about 60% to about 90%, about 70% toabout 90%, about 10% to about 80%, about 20% to about 80%, about 30% toabout 80%, about 40% to about 80%, about 50% to about 80%, or about 60%to about 80%, about 10% to about 70%, about 20% to about 70%, about 30%to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein havingantitussive activity reduces the severity of a cough. In aspects of thisembodiment, a therapeutic compound having antitussive activity reducesthe severity of a cough by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In other aspects of this embodiment, a therapeutic compound havingantitussive activity reduces the severity of a cough by, e.g., about 10%to about 100%, about 20% to about 100%, about 30% to about 100%, about40% to about 100%, about 50% to about 100%, about 60% to about 100%,about 70% to about 100%, about 80% to about 100%, about 10% to about90%, about 20% to about 90%, about 30% to about 90%, about 40% to about90%, about 50% to about 90%, about 60% to about 90%, about 70% to about90%, about 10% to about 80%, about 20% to about 80%, about 30% to about80%, about 40% to about 80%, about 50% to about 80%, or about 60% toabout 80%, about 10% to about 70%, about 20% to about 70%, about 30% toabout 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein havingantitussive activity reduces muscle spasms associated with a cough. Inaspects of this embodiment, a therapeutic compound having antitussiveactivity reduces muscle spasms associated with a cough by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In other aspects of thisembodiment, a therapeutic compound having antitussive activity reducesmuscle spasms associated with a cough by, e.g., about 10% to about 100%,about 20% to about 100%, about 30% to about 100%, about 40% to about100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 100%, about 80% to about 100%, about 10% to about 90%, about 20%to about 90%, about 30% to about 90%, about 40% to about 90%, about 50%to about 90%, about 60% to about 90%, about 70% to about 90%, about 10%to about 80%, about 20% to about 80%, about 30% to about 80%, about 40%to about 80%, about 50% to about 80%, or about 60% to about 80%, about10% to about 70%, about 20% to about 70%, about 30% to about 70%, about40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein havingantitussive activity reduces the volume or noise level of a cough. Inaspects of this embodiment, a therapeutic compound having antitussiveactivity reduces the volume or noise level of a cough by, e.g., at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90% or at least 95%. In other aspects of this embodiment,a therapeutic compound having antitussive activity reduces the volume ornoise level of a cough by, e.g., about 10% to about 100%, about 20% toabout 100%, about 30% to about 100%, about 40% to about 100%, about 50%to about 100%, about 60% to about 100%, about 70% to about 100%, about80% to about 100%, about 10% to about 90%, about 20% to about 90%, about30% to about 90%, about 40% to about 90%, about 50% to about 90%, about60% to about 90%, about 70% to about 90%, about 10% to about 80%, about20% to about 80%, about 30% to about 80%, about 40% to about 80%, about50% to about 80%, or about 60% to about 80%, about 10% to about 70%,about 20% to about 70%, about 30% to about 70%, about 40% to about 70%,or about 50% to about 70%.

The coughing mechanism is a reflex arc that is initiated by stimulationof sensory nerve fibers belonging to branches of the vagal nervedistributed throughout the respiratory tract with greatest concentrationin the upper airways. There fibers respond to chemical and/or mechanicalstimuli. After stimulation, impulses travel away along nerves (afferentlimb), to intermediate nerve terminal ganglions, where connecting nervesintersect to further transmit impulses to the cough center in themedulla. In the brain, all nerve impulses are integrated, and acoordinated set of nerve impulses are generated to nerves (efferentlimb) leading to the expiratory muscles that contract to produce aneffective cough. A pharmaceutical composition or a therapeutic compounddisclosed herein have an antitussive effect that may work at one or at acombination of sites along the reflex arc.

In one embodiment, a therapeutic compound disclosed herein havingantitussive activity suppresses a vagal nerve function associated with acough. In aspects of this embodiment, a therapeutic compound havingantitussive activity suppresses vagal nerve function associated with acough by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In other aspectsof this embodiment, a therapeutic compound having antitussive activitysuppresses vagal nerve function associated with a cough by, e.g., about10% to about 100%, about 20% to about 100%, about 30% to about 100%,about 40% to about 100%, about 50% to about 100%, about 60% to about100%, about 70% to about 100%, about 80% to about 100%, about 10% toabout 90%, about 20% to about 90%, about 30% to about 90%, about 40% toabout 90%, about 50% to about 90%, about 60% to about 90%, about 70% toabout 90%, about 10% to about 80%, about 20% to about 80%, about 30% toabout 80%, about 40% to about 80%, about 50% to about 80%, or about 60%to about 80%, about 10% to about 70%, about 20% to about 70%, about 30%to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein havingantitussive activity suppresses a central nerve function associated witha cough. In aspects of this embodiment, a therapeutic compound havingantitussive activity suppresses central nerve function associated with acough by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In other aspectsof this embodiment, a therapeutic compound having antitussive activitysuppresses central nerve function associated with a cough by, e.g.,about 10% to about 100%, about 20% to about 100%, about 30% to about100%, about 40% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100%, about 10%to about 90%, about 20% to about 90%, about 30% to about 90%, about 40%to about 90%, about 50% to about 90%, about 60% to about 90%, about 70%to about 90%, about 10% to about 80%, about 20% to about 80%, about 30%to about 80%, about 40% to about 80%, about 50% to about 80%, or about60% to about 80%, about 10% to about 70%, about 20% to about 70%, about30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein havingantitussive activity suppresses a peripheral nerve function associatedwith a cough. In aspects of this embodiment, a therapeutic compoundhaving antitussive activity suppresses peripheral nerve functionassociated with a cough by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In other aspects of this embodiment, a therapeutic compound havingantitussive activity suppresses peripheral nerve function associatedwith a cough by, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

A therapeutic compound disclosed herein may be a cocoa. In aspects ofthis embodiment, the cocoa may be a cocoa powder, a cocoa liquid, or anyother suitable form of cocoa. In aspects of this embodiment, apharmaceutical composition comprises cocoa is in an amount of, e.g.,about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 18%, or about 20%of the total weight or volume of the pharmaceutical composition. Inother aspects of this embodiment, a pharmaceutical composition comprisescocoa is in an amount of, e.g., at least 1%, at least 2%, at least 3%,at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, atleast 9%, at least 10%, at least 11%, at least 12%, at least 13%, atleast 14%, at least 15%, at least 16%, at least 17%, at least 18%, atleast 18%, or at least 20% of the total weight or volume of thepharmaceutical composition. In yet other aspects of this embodiment, apharmaceutical composition comprises cocoa is in an amount of, e.g., atmost 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, atmost 7%, at most 8%, at most 9%, at most 10%, at most 11%, at most 12%,at most 13%, at most 14%, at most 15%, at most 16%, at most 17%, at most18%, at most 18%, or at most 20% of the total weight or volume of thepharmaceutical composition. In still other aspects of this embodiment, apharmaceutical composition comprises cocoa is in an amount of, e.g.,about 1% to about 3%, about 1% to about 5%, about 1% to about 7%, about1% to about 10%, about 1% to about 12%, about 1% to about 15%, about 1%to about 18%, about 1% to about 20%, about 2% to about 3%, about 2% toabout 5%, about 2% to about 7%, about 2% to about 10%, about 2% to about12%, about 2% to about 15%, about 2% to about 18%, about 2% to about20%, about 3% to about 5%, about 3% to about 7%, about 3% to about 10%,about 3% to about 12%, about 3% to about 15%, about 3% to about 18%,about 3% to about 20%, about 5% to about 7%, about 5% to about 10%,about 5% to about 12%, about 5% to about 15%, about 5% to about 18%,about 5% to about 20%, about 7% to about 10%, about 7% to about 12%,about 7% to about 15%, about 7% to about 18%, about 7% to about 20%,about 8% to about 10%, about 8% to about 12%, about 8% to about 15%,about 8% to about 18%, about 8% to about 20%, about 10% to about 12%,about 10% to about 15%, about 10% to about 18%, about 10% to about 20%,bout 12% to about 15%, about 12% to about 18%, about 12% to about 20%,about 15% to about 18%, about 15% to about 20%, or about 18% to about20%.

A therapeutic compound disclosed herein may be a methylxanthine. As usedherein, the term “methylxanthine” refers to a class of therapeuticcompounds composed of various purines having two oxygen atoms attachedto the six-member ring of carbon and nitrogen atoms that act as a smoothmuscle relaxant, vasodilator, and/or diuretic. Methylxanthines act asbronchodilators by relaxing bronchial smooth muscles, thereby dilatinginflamed or otherwise constricted respiratory tract airways.Methylxanthines are 1) competitive nonselective phosphodiesteraseinhibitor which raise intracellular cAMP, activate PKA, inhibit TNF-α,and inhibit leukotriene synthesis, thereby reducing inflammation andinnate immunity; and 2) nonselective adenosine receptor antagonist,blocking A1, A2, and A3 receptors, thereby inhibiting thebronchoconstriction and sleepiness-inducing effects of adenosine.Methylxanthines naturally occur in as many as sixty different plantspecies including the coffee plant, cacao plant, tea plant, and the kola(or cola) plant. Examples of suitable methylxanthines include, withoutlimitation, Aminophylline, Caffeine(1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione), IBMX, Paraxanthine,Pentoxifylline, Theobromine(3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione), Theophylline(1,3-dimethyl-7H-purine-2,6-dione) and Xanthine(3,7-dihydro-purine-2,6-dione).

A methylxanthine may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprisesmethylxanthine in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL,about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, or about 30 mg/mL In other aspects of this embodiment, apharmaceutical composition comprises methylxanthine in an amount of,e.g., about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL,about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275mg/mL, about 300 mg/mL, about 325 mg/mL, about 350 mg/mL, about 375mg/mL, about 400 mg/mL, about 425 mg/mL, about 450 mg/mL, about 475mg/mL, about 500 mg/mL, about 525 mg/mL, about 550 mg/mL, about 575mg/mL, about 600 mg/mL, about 625 mg/mL, about 650 mg/mL, about 675mg/mL, about 700 mg/mL, about 725 mg/mL, about 750 mg/mL, about 775mg/mL, about 800 mg/mL, about 825 mg/mL, about 850 mg/mL, about 875mg/mL, about 900 mg/mL, about 925 mg/mL, about 950 mg/mL, about 975mg/mL, or about 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises methylxanthine in an amount of, e.g., at least 0.1 mg/mL, atleast 0.2 mg/mL, at least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5mg/mL, at least 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, atleast 0.9 mg/mL, at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL,at least 4 mg/mL, at least 5 mg/mL, at least 6 mg/mL, at least 7 mg/mL,at least 8 mg/mL, at least 9 mg/mL, at least 10 mg/mL, at least 11mg/mL, at least 12 mg/mL, at least 13 mg/mL, at least 14 mg/mL, at least15 mg/mL, at least 16 mg/mL, at least 17 mg/mL, at least 18 mg/mL, atleast 19 mg/mL, at least 20 mg/mL, at least 21 mg/mL, at least 22 mg/mL,at least 23 mg/mL, at least 24 mg/mL, at least 25 mg/mL, at least 26mg/mL, at least 27 mg/mL, at least 28 mg/mL, at least 29 mg/mL, or atleast 30 mg/mL In aspects of this embodiment, a pharmaceuticalcomposition comprises methylxanthine in an amount of, e.g., at least 10mg/mL, at least 20 mg/mL, at least 30 mg/mL, at least 40 mg/mL, at least50 mg/mL, at least 60 mg/mL, at least 70 mg/mL, at least 80 mg/mL, atleast 90 mg/mL, at least 100 mg/mL, at least 125 mg/mL, at least 150mg/mL, at least 175 mg/mL, at least 200 mg/mL, at least 225 mg/mL, atleast 250 mg/mL, at least 275 mg/mL, at least 300 mg/mL, at least 325mg/mL, at least 350 mg/mL, at least 375 mg/mL, at least 400 mg/mL, atleast 425 mg/mL, at least 450 mg/mL, at least 475 mg/mL, at least 500mg/mL, at least 525 mg/mL, at least 550 mg/mL, at least 575 mg/mL, atleast 600 mg/mL, at least 625 mg/mL, at least 650 mg/mL, at least 675mg/mL, at least 700 mg/mL, at least 725 mg/mL, at least 750 mg/mL, atleast 775 mg/mL, at least 800 mg/mL, at least 825 mg/mL, at least 850mg/mL, at least 875 mg/mL, at least 900 mg/mL, at least 925 mg/mL, atleast 950 mg/mL, at least 975 mg/mL, or at least 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises methylxanthine in an amount of, e.g., at most 0.1 mg/mL, atmost 0.2 mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL,at most 0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9mg/mL, at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4mg/mL, at most 5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8mg/mL, at most 9 mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12mg/mL, at most 13 mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16mg/mL, at most 17 mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20mg/mL, at most 21 mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24mg/mL, at most 25 mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28mg/mL, at most 29 mg/mL, or at most 30 mg/mL In yet other aspects ofthis embodiment, a pharmaceutical composition comprises methylxanthinein an amount of, e.g., at most 10 mg/mL, at most 20 mg/mL, at most 30mg/mL, at most 40 mg/mL, at most 50 mg/mL, at most 60 mg/mL, at most 70mg/mL, at most 80 mg/mL, at most 90 mg/mL, at most 100 mg/mL, at most125 mg/mL, at most 150 mg/mL, at most 175 mg/mL, at most 200 mg/mL, atmost 225 mg/mL, at most 250 mg/mL, at most 275 mg/mL, at most 300 mg/mL,at most 325 mg/mL, at most 350 mg/mL, at most 375 mg/mL, at most 400mg/mL, at most 425 mg/mL, at most 450 mg/mL, at most 475 mg/mL, at most500 mg/mL, at most 525 mg/mL, at most 550 mg/mL, at most 575 mg/mL, atmost 600 mg/mL, at most 625 mg/mL, at most 650 mg/mL, at most 675 mg/mL,at most 700 mg/mL, at most 725 mg/mL, at most 750 mg/mL, at most 775mg/mL, at most 800 mg/mL, at most 825 mg/mL, at most 850 mg/mL, at most875 mg/mL, at most 900 mg/mL, at most 925 mg/mL, at most 950 mg/mL, atmost 975 mg/mL, or at most 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises methylxanthine in an amount of, e.g., about 0.1 mg/mL to about1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL to about 3mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL to about 7mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL to about 9mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 1mg/mL, about 0.5 mg/mL to about 2 mg/mL, about 0.5 mg/mL to about 3mg/mL, about 0.5 mg/mL to about 4 mg/mL, about 0.5 mg/mL to about 5mg/mL, about 0.5 mg/mL to about 6 mg/mL, about 0.5 mg/mL to about 7mg/mL, about 0.5 mg/mL to about 8 mg/mL, about 0.5 mg/mL to about 9mg/mL, about 0.5 mg/mL to about 10 mg/mL, about 1 mg/mL to about 5mg/mL, about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 15 mg/mL,about 1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 25 mg/mL, about1 mg/mL to about 30 mg/mL, about 1 mg/mL to about 35 mg/mL, about 1mg/mL to about 40 mg/mL, about 1 mg/mL to about 45 mg/mL, about 1 mg/mLto about 50 mg/mL, about 5 mg/mL to about 10 mg/mL, about 5 mg/mL toabout 15 mg/mL, about 5 mg/mL to about 20 mg/mL, about 5 mg/mL to about25 mg/mL, about 5 mg/mL to about 30 mg/mL, about 5 mg/mL to about 35mg/mL, about 5 mg/mL to about 40 mg/mL, about 5 mg/mL to about 45 mg/mL,about 5 mg/mL to about 50 mg/mL, about 10 mg/mL to about 20 mg/mL, about10 mg/mL to about 30 mg/mL, about 10 mg/mL to about 40 mg/mL, about 10mg/mL to about 50 mg/mL, about 10 mg/mL to about 60 mg/mL, about 10mg/mL to about 70 mg/mL, about 10 mg/mL to about 80 mg/mL, about 10mg/mL to about 90 mg/mL, about 10 mg/mL to about 100 mg/mL, about 25mg/mL to about 50 mg/mL, about 25 mg/mL to about 75 mg/mL, about 25mg/mL to about 100 mg/mL, about 25 mg/mL to about 125 mg/mL, about 25mg/mL to about 150 mg/mL, about 25 mg/mL to about 175 mg/mL, about 25mg/mL to about 200 mg/mL, about 25 mg/mL to about 225 mg/mL, about 25mg/mL to about 250 mg/mL, about 50 mg/mL to about 75 mg/mL, about 50mg/mL to about 100 mg/mL, about 50 mg/mL to about 125 mg/mL, about 50mg/mL to about 150 mg/mL, about 50 mg/mL to about 175 mg/mL, about 50mg/mL to about 200 mg/mL, about 50 mg/mL to about 225 mg/mL, about 50mg/mL to about 250 mg/mL, about 50 mg/mL to about 275 mg/mL, about 50mg/mL to about 300 mg/mL, about 50 mg/mL to about 325 mg/mL, about 50mg/mL to about 350 mg/mL, about 50 mg/mL to about 375 mg/mL, about 50mg/mL to about 400 mg/mL, about 50 mg/mL to about 425 mg/mL, about 50mg/mL to about 450 mg/mL, about 50 mg/mL to about 475 mg/mL, about 50mg/mL to about 500 mg/mL, about 100 mg/mL to about 150 mg/mL, about 100mg/mL to about 200 mg/mL, about 100 mg/mL to about 250 mg/mL, about 100mg/mL to about 300 mg/mL, about 100 mg/mL to about 350 mg/mL, about 100mg/mL to about 400 mg/mL, about 100 mg/mL to about 450 mg/mL, about 100mg/mL to about 500 mg/mL, about 200 mg/mL to about 300 mg/mL, about 200mg/mL to about 400 mg/mL, about 200 mg/mL to about 500 mg/mL, about 200mg/mL to about 600 mg/mL, about 200 mg/mL to about 700 mg/mL, about 200mg/mL to about 800 mg/mL, about 200 mg/mL to about 900 mg/mL, or about200 mg/mL to about 1000 mg/mL.

A theobromine may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprises atheobromine in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL,about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, or about 30 mg/mL In other aspects of this embodiment, apharmaceutical composition comprises a theobromine in an amount of,e.g., about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL,about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275mg/mL, about 300 mg/mL, about 325 mg/mL, about 350 mg/mL, about 375mg/mL, about 400 mg/mL, about 425 mg/mL, about 450 mg/mL, about 475mg/mL, about 500 mg/mL, about 525 mg/mL, about 550 mg/mL, about 575mg/mL, about 600 mg/mL, about 625 mg/mL, about 650 mg/mL, about 675mg/mL, about 700 mg/mL, about 725 mg/mL, about 750 mg/mL, about 775mg/mL, about 800 mg/mL, about 825 mg/mL, about 850 mg/mL, about 875mg/mL, about 900 mg/mL, about 925 mg/mL, about 950 mg/mL, about 975mg/mL, or about 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises a theobromine in an amount of, e.g., at least 0.1 mg/mL, atleast 0.2 mg/mL, at least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5mg/mL, at least 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, atleast 0.9 mg/mL, at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL,at least 4 mg/mL, at least 5 mg/mL, at least 6 mg/mL, at least 7 mg/mL,at least 8 mg/mL, at least 9 mg/mL, at least 10 mg/mL, at least 11mg/mL, at least 12 mg/mL, at least 13 mg/mL, at least 14 mg/mL, at least15 mg/mL, at least 16 mg/mL, at least 17 mg/mL, at least 18 mg/mL, atleast 19 mg/mL, at least 20 mg/mL, at least 21 mg/mL, at least 22 mg/mL,at least 23 mg/mL, at least 24 mg/mL, at least 25 mg/mL, at least 26mg/mL, at least 27 mg/mL, at least 28 mg/mL, at least 29 mg/mL, or atleast 30 mg/mL In aspects of this embodiment, a pharmaceuticalcomposition comprises theobromine in an amount of, e.g., at least 10mg/mL, at least 20 mg/mL, at least 30 mg/mL, at least 40 mg/mL, at least50 mg/mL, at least 60 mg/mL, at least 70 mg/mL, at least 80 mg/mL, atleast 90 mg/mL, at least 100 mg/mL, at least 125 mg/mL, at least 150mg/mL, at least 175 mg/mL, at least 200 mg/mL, at least 225 mg/mL, atleast 250 mg/mL, at least 275 mg/mL, at least 300 mg/mL, at least 325mg/mL, at least 350 mg/mL, at least 375 mg/mL, at least 400 mg/mL, atleast 425 mg/mL, at least 450 mg/mL, at least 475 mg/mL, at least 500mg/mL, at least 525 mg/mL, at least 550 mg/mL, at least 575 mg/mL, atleast 600 mg/mL, at least 625 mg/mL, at least 650 mg/mL, at least 675mg/mL, at least 700 mg/mL, at least 725 mg/mL, at least 750 mg/mL, atleast 775 mg/mL, at least 800 mg/mL, at least 825 mg/mL, at least 850mg/mL, at least 875 mg/mL, at least 900 mg/mL, at least 925 mg/mL, atleast 950 mg/mL, at least 975 mg/mL, or at least 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises a theobromine in an amount of, e.g., at most 0.1 mg/mL, atmost 0.2 mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL,at most 0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9mg/mL, at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4mg/mL, at most 5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8mg/mL, at most 9 mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12mg/mL, at most 13 mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16mg/mL, at most 17 mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20mg/mL, at most 21 mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24mg/mL, at most 25 mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28mg/mL, at most 29 mg/mL, or at most 30 mg/mL In yet other aspects ofthis embodiment, a theobromine is in an amount of, e.g., at most 10mg/mL, at most 20 mg/mL, at most 30 mg/mL, at most 40 mg/mL, at most 50mg/mL, at most 60 mg/mL, at most 70 mg/mL, at most 80 mg/mL, at most 90mg/mL, at most 100 mg/mL, at most 125 mg/mL, at most 150 mg/mL, at most175 mg/mL, at most 200 mg/mL, at most 225 mg/mL, at most 250 mg/mL, atmost 275 mg/mL, at most 300 mg/mL, at most 325 mg/mL, at most 350 mg/mL,at most 375 mg/mL, at most 400 mg/mL, at most 425 mg/mL, at most 450mg/mL, at most 475 mg/mL, at most 500 mg/mL, at most 525 mg/mL, at most550 mg/mL, at most 575 mg/mL, at most 600 mg/mL, at most 625 mg/mL, atmost 650 mg/mL, at most 675 mg/mL, at most 700 mg/mL, at most 725 mg/mL,at most 750 mg/mL, at most 775 mg/mL, at most 800 mg/mL, at most 825mg/mL, at most 850 mg/mL, at most 875 mg/mL, at most 900 mg/mL, at most925 mg/mL, at most 950 mg/mL, at most 975 mg/mL, or at most 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises a theobromine in an amount of, e.g., about 0.1 mg/mL to about1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL to about 3mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL to about 7mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL to about 9mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 1mg/mL, about 0.5 mg/mL to about 2 mg/mL, about 0.5 mg/mL to about 3mg/mL, about 0.5 mg/mL to about 4 mg/mL, about 0.5 mg/mL to about 5mg/mL, about 0.5 mg/mL to about 6 mg/mL, about 0.5 mg/mL to about 7mg/mL, about 0.5 mg/mL to about 8 mg/mL, about 0.5 mg/mL to about 9mg/mL, about 0.5 mg/mL to about 10 mg/mL, about 1 mg/mL to about 2mg/mL, about 1 mg/mL to about 3 mg/mL, about 1 mg/mL to about 4 mg/mL,about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 6 mg/mL, about 1mg/mL to about 7 mg/mL, about 1 mg/mL to about 8 mg/mL, about 1 mg/mL toabout 9 mg/mL, about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about15 mg/mL, about 1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 25mg/mL, about 1 mg/mL to about 30 mg/mL, about 1 mg/mL to about 35 mg/mL,about 1 mg/mL to about 40 mg/mL, about 1 mg/mL to about 45 mg/mL, about1 mg/mL to about 50 mg/mL, about 5 mg/mL to about 10 mg/mL, about 5mg/mL to about 15 mg/mL, about 5 mg/mL to about 20 mg/mL, about 5 mg/mLto about 25 mg/mL, about 5 mg/mL to about 30 mg/mL, about 5 mg/mL toabout 35 mg/mL, about 5 mg/mL to about 40 mg/mL, about 5 mg/mL to about45 mg/mL, about 5 mg/mL to about 50 mg/mL, about 10 mg/mL to about 20mg/mL, about 10 mg/mL to about 30 mg/mL, about 10 mg/mL to about 40mg/mL, about 10 mg/mL to about 50 mg/mL, about 10 mg/mL to about 60mg/mL, about 10 mg/mL to about 70 mg/mL, about 10 mg/mL to about 80mg/mL, about 10 mg/mL to about 90 mg/mL, about 10 mg/mL to about 100mg/mL, about 25 mg/mL to about 50 mg/mL, about 25 mg/mL to about 75mg/mL, about 25 mg/mL to about 100 mg/mL, about 25 mg/mL to about 125mg/mL, about 25 mg/mL to about 150 mg/mL, about 25 mg/mL to about 175mg/mL, about 25 mg/mL to about 200 mg/mL, about 25 mg/mL to about 225mg/mL, about 25 mg/mL to about 250 mg/mL, about 50 mg/mL to about 75mg/mL, about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to about 125mg/mL, about 50 mg/mL to about 150 mg/mL, about 50 mg/mL to about 175mg/mL, about 50 mg/mL to about 200 mg/mL, about 50 mg/mL to about 225mg/mL, about 50 mg/mL to about 250 mg/mL, about 50 mg/mL to about 275mg/mL, about 50 mg/mL to about 300 mg/mL, about 50 mg/mL to about 325mg/mL, about 50 mg/mL to about 350 mg/mL, about 50 mg/mL to about 375mg/mL, about 50 mg/mL to about 400 mg/mL, about 50 mg/mL to about 425mg/mL, about 50 mg/mL to about 450 mg/mL, about 50 mg/mL to about 475mg/mL, about 50 mg/mL to about 500 mg/mL, about 100 mg/mL to about 150mg/mL, about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 250mg/mL, about 100 mg/mL to about 300 mg/mL, about 100 mg/mL to about 350mg/mL, about 100 mg/mL to about 400 mg/mL, about 100 mg/mL to about 450mg/mL, about 100 mg/mL to about 500 mg/mL, about 200 mg/mL to about 300mg/mL, about 200 mg/mL to about 400 mg/mL, about 200 mg/mL to about 500mg/mL, about 200 mg/mL to about 600 mg/mL, about 200 mg/mL to about 700mg/mL, about 200 mg/mL to about 800 mg/mL, about 200 mg/mL to about 900mg/mL, or about 200 mg/mL to about 1000 mg/mL.

A therapeutic compound disclosed herein may be a non-opiate antitussiveagent. As used herein, the term “non-opiate antitussive agent” refers toa class of non-opioid-based therapeutic compounds that act on thecentral and peripheral nervous systems to suppress the cough reflex. Anon-opiate antitussive agent is preferably an NMDA antagonist. Examplesof suitable non-opiate antitussive agents include, without limitation,Benproperine, Benzonate, Bibenzonium, Butamirate, Cloperastine,Clofedanol, Dextromethorphan, Dibunate, Dimemorfan, Dropropizine,Fedrilate, Indantadol, Isoaminile, Morclofone, Meprotixol, Nepinalone,Oxolamine, Oxeladin, Piperidione, Pentoxyverine, Prenoxdiazine, andZipeprol.

A non-opiate antitussive agent may be in an amount suitable for itsintended use. In aspects of this embodiment, a pharmaceuticalcomposition comprises a non-opiate antitussive agent in an amount of,e.g., about 0.1 mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7mg/mL, about 0.75 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL,about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL,about 20 mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL,about 29 mg/mL, or about 30 mg/mL. In other aspects of this embodiment,a pharmaceutical composition comprises a non-opiate antitussive agent inan amount of, e.g., at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, atleast 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9 mg/mL, at least 1mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8 mg/mL, at least 9mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least 12 mg/mL, at least13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, atleast 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL, at least 20 mg/mL,at least 21 mg/mL, at least 22 mg/mL, at least 23 mg/mL, at least 24mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least 27 mg/mL, at least28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL. In yet other aspectsof this embodiment, a pharmaceutical composition comprises a non-opiateantitussive agent in an amount of, e.g., at most 0.1 mg/mL, at most 0.2mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, atmost 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises a non-opiate antitussive agent in an amount of, e.g., about0.1 mg/mL to about 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1mg/mL to about 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1mg/mL to about 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1mg/mL to about 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25mg/mL to about 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25mg/mL to about 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25mg/mL to about 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25mg/mL to about 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25mg/mL to about 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5mg/mL to about 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5mg/mL to about 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5mg/mL to about 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5mg/mL to about 7.5 mg/mL, about 0.5 mg/mL to about 8 mg/mL, about 0.5mg/mL to about 9 mg/mL, about 0.5 mg/mL to about 10 mg/mL, about 0.75mg/mL to about 1 mg/mL, about 0.75 mg/mL to about 2 mg/mL, about 0.75mg/mL to about 3 mg/mL, about 0.75 mg/mL to about 4 mg/mL, about 0.75mg/mL to about 5 mg/mL, about 0.75 mg/mL to about 6 mg/mL, about 0.75mg/mL to about 7 mg/mL, about 0.75 mg/mL to about 8 mg/mL, about 0.75mg/mL to about 9 mg/mL, about 0.75 mg/mL to about 10 mg/mL, about 1mg/mL to about 2 mg/mL, about 1 mg/mL to about 3 mg/mL, about 1 mg/mL toabout 4 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 6mg/mL, about 1 mg/mL to about 7 mg/mL, about 1 mg/mL to about 8 mg/mL,about 1 mg/mL to about 9 mg/mL, about 1 mg/mL to about 10 mg/mL, about 1mg/mL to about 15 mg/mL, about 1 mg/mL to about 20 mg/mL, about 1 mg/mLto about 25 mg/mL, about 1 mg/mL to about 30 mg/mL, about 5 mg/mL toabout 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about 5 mg/mL to about20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL to about 30mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10 mg/mL to about 30mg/mL.

A therapeutic compound disclosed herein may be an opiate antitussiveagent. As used herein, the term “opiate antitussive agent” refers to aclass of opioid-based therapeutic compounds that act on the central andperipheral nervous systems to suppress the cough reflex. Examples ofsuitable opiates include, without limitation, Alfentanil,Alphamethylfentanyl, Buprenorphine, Carfentanyl, Codeine, Diamorphine,Dihydrocodeine, Ethyl Morphine, Etorphine, Fentanyl, Hydrocodone,Hydromorphone, Loperamide, Morphine, Noscapine, Oripavine, Oxymorphone,Oxycodone, Papaverine, Pentazocine, Pethidine, Propoxyphene,Remifentanil, Sufentanil, Thebaine, Tipepidine, and Tramadol.

An opiate antitussive agent may be in an amount suitable for itsintended use. In aspects of this embodiment, a pharmaceuticalcomposition comprises an opiate antitussive agent in an amount of, e.g.,about 0.1 mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL,about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL,about 0.75 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, or about 30 mg/mL. In other aspects of this embodiment, apharmaceutical composition comprises an opiate antitussive agent in anamount of, e.g., at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, atleast 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9 mg/mL, at least 1mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8 mg/mL, at least 9mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least 12 mg/mL, at least13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, atleast 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL, at least 20 mg/mL,at least 21 mg/mL, at least 22 mg/mL, at least 23 mg/mL, at least 24mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least 27 mg/mL, at least28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL. In yet other aspectsof this embodiment, a pharmaceutical composition comprises an opiateantitussive agent in an amount of, e.g., at most 0.1 mg/mL, at most 0.2mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, atmost 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises an opiate antitussive agent in an amount of, e.g., about 0.1mg/mL to about 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1mg/mL to about 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1mg/mL to about 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1mg/mL to about 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25mg/mL to about 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25mg/mL to about 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25mg/mL to about 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25mg/mL to about 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25mg/mL to about 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5mg/mL to about 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5mg/mL to about 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5mg/mL to about 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5mg/mL to about 8 mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5mg/mL to about 10 mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75mg/mL to about 2 mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75mg/mL to about 4 mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75mg/mL to about 6 mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75mg/mL to about 8 mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75mg/mL to about 10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mLto about 10 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL toabout 20 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about30 mg/mL, about 5 mg/mL to about 10 mg/mL, about 5 mg/mL to about 15mg/mL, about 5 mg/mL to about 20 mg/mL, about 5 mg/mL to about 25 mg/mL,about 5 mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, orabout 10 mg/mL to about 30 mg/mL.

A therapeutic compound disclosed herein may be a decongestant. As usedherein, the term “decongestant” refers to a class of therapeuticcompounds that promote the secretion, liquefaction, or expulsion ofsputum of phlegm or mucus from the respiratory tract. Decongestants actby causing the inflamed blood vessels in the nose and sinuses toconstrict, thereby reducing inflammation and mucus formation. Adecongestant is preferably an α-adrenergic receptor agonist. Examples ofsuitable decongestants include, without limitation, Ephedrine,Levmetamfetamine, Naphazoline, Oxymetazoline, Phenylephrine,Phenylpropanolamine, Propylhexedrine, Pseudoephedrine, Synephrine, andTetrahydrozoline.

A decongestant may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprises adecongestant in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.25 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL,about 0.6 mg/mL, about 0.7 mg/mL, about 0.75 mg/mL, about 0.8 mg/mL,about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL,about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL, about 22 mg/mL,about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27mg/mL, about 28 mg/mL, about 29 mg/mL, or about 30 mg/mL. In otheraspects of this embodiment, a pharmaceutical composition comprises adecongestant in an amount of, e.g., at least 0.1 mg/mL, at least 0.2mg/mL, at least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL, atleast 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9mg/mL, at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4mg/mL, at least 5 mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8mg/mL, at least 9 mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least12 mg/mL, at least 13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, atleast 16 mg/mL, at least 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL,at least 20 mg/mL, at least 21 mg/mL, at least 22 mg/mL, at least 23mg/mL, at least 24 mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least27 mg/mL, at least 28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL. Inyet other aspects of this embodiment, a pharmaceutical compositioncomprises a decongestant in an amount of, e.g., at most 0.1 mg/mL, atmost 0.2 mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL,at most 0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9mg/mL, at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4mg/mL, at most 5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8mg/mL, at most 9 mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12mg/mL, at most 13 mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16mg/mL, at most 17 mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20mg/mL, at most 21 mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24mg/mL, at most 25 mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28mg/mL, at most 29 mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises a decongestant in an amount of, e.g., about 0.1 mg/mL to about1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL to about 3mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL to about 7mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL to about 9mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL to about 1mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL to about 3mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL to about 5mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL to about 7mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL to about 8mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL to about 10mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL to about 2mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL to about 4mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL to about 6mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL to about 8mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL to about 10mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75 mg/mL to about 2mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75 mg/mL to about 4mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75 mg/mL to about 6mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75 mg/mL to about 8mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75 mg/mL to about 10mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 10 mg/mL,about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20 mg/mL, about1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL, about 5mg/mL to about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about 5 mg/mLto about 20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL toabout 30 mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10 mg/mL toabout 30 mg/mL.

A therapeutic compound disclosed herein may be an expectorant. As usedherein, the term “expectorant” refers to a class of therapeuticcompounds that promote the secretion, liquefaction, or expulsion ofsputum of phlegm or mucus from the respiratory tract. Expectorants workby breaking the bonds between mucoproteins that create the thickness orviscosity of mucus in the respiratory tract, thereby increasing mucusflow and making it easier to remove from the body through coughing.Examples of suitable expectorants include, without limitation, Ambroxol,Ammonium Bicarbonate, Ammonium Carbonate, Bromhexine, Calcium Iodide,Carbocysteine, Guaiacol, Guaicacol Benzoate, Guaiacol Carbonate,Guaiacol Phosphate, Guaifenesin, Guaithylline, Hydriodic Acid, IodinatedGlycerol, Potassium Guaiacolsulfonate, Potassium Iodide, Sodium Citrate,Sodium Iodide, Storax Terebene, Terpin, Trifolium, Althea Root, AntimonyPentasulfide, Creosote, Ipecacuanha (Syrup of Ipecac), Levoverbenone,Senega, and Tyloxapol.

An expectorant may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprises anexpectorant in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL,about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, or about 30 mg/mL. In other aspects of this embodiment, apharmaceutical composition comprises an expectorant in an amount of,e.g., at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3 mg/mL, atleast 0.4 mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, at least 0.7mg/mL, at least 0.8 mg/mL, at least 0.9 mg/mL, at least 1 mg/mL, atleast 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, atleast 6 mg/mL, at least 7 mg/mL, at least 8 mg/mL, at least 9 mg/mL, atleast 10 mg/mL, at least 11 mg/mL, at least 12 mg/mL, at least 13 mg/mL,at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, at least 17mg/mL, at least 18 mg/mL, at least 19 mg/mL, at least 20 mg/mL, at least21 mg/mL, at least 22 mg/mL, at least 23 mg/mL, at least 24 mg/mL, atleast 25 mg/mL, at least 26 mg/mL, at least 27 mg/mL, at least 28 mg/mL,at least 29 mg/mL, or at least 30 mg/mL. In yet other aspects of thisembodiment, a pharmaceutical composition comprises an expectorant in anamount of, e.g., at most 0.1 mg/mL, at most 0.2 mg/mL, at most 0.3mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most 0.6 mg/mL, at most0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, at most 1 mg/mL, atmost 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most 5 mg/mL, at most6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9 mg/mL, at most 10mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13 mg/mL, at most 14mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17 mg/mL, at most 18mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21 mg/mL, at most 22mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25 mg/mL, at most 26mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29 mg/mL, or at most30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises an expectorant in an amount of, e.g., about 0.1 mg/mL to about1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL to about 3mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL to about 7mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL to about 9mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL to about 1mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL to about 3mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL to about 5mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL to about 7mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL to about 8mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL to about 10mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL to about 2mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL to about 4mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL to about 6mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL to about 8mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL to about 10mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75 mg/mL to about 2mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75 mg/mL to about 4mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75 mg/mL to about 6mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75 mg/mL to about 8mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75 mg/mL to about 10mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 10 mg/mL,about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20 mg/mL, about1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL, about 5mg/mL to about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about 5 mg/mLto about 20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL toabout 30 mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10 mg/mL toabout 30 mg/mL.

A therapeutic compound disclosed herein may be a mucolytic agent. Asused herein, the term “mucolytic agent” refers to a class of therapeuticcompounds that promote the secretion, liquefaction, or expulsion ofsputum of phlegm or mucus from the respiratory tract. Examples ofsuitable mucolytic agents include, without limitation, Acetylcysteine,Bromhexine, Carbocysteine, Domiodol, Erdostine, Letostine, Lysozyme,Mecysteine Hydrochloride, Mesna, Sobrerol, Stepronin, Tiopronin,Tyloxapol, Ambroxol, Ammonium Chloride, Dornase Alfa, Eprazinone,Erdosteine, Letosteine, and Neltenexine.

A mucolytic agent may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprises amucolytic agent in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL,about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, or about 30 mg/mL. In other aspects of this embodiment, apharmaceutical composition comprises a mucolytic agent in an amount of,e.g., at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3 mg/mL, atleast 0.4 mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, at least 0.7mg/mL, at least 0.8 mg/mL, at least 0.9 mg/mL, at least 1 mg/mL, atleast 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, atleast 6 mg/mL, at least 7 mg/mL, at least 8 mg/mL, at least 9 mg/mL, atleast 10 mg/mL, at least 11 mg/mL, at least 12 mg/mL, at least 13 mg/mL,at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, at least 17mg/mL, at least 18 mg/mL, at least 19 mg/mL, at least 20 mg/mL, at least21 mg/mL, at least 22 mg/mL, at least 23 mg/mL, at least 24 mg/mL, atleast 25 mg/mL, at least 26 mg/mL, at least 27 mg/mL, at least 28 mg/mL,at least 29 mg/mL, or at least 30 mg/mL. In yet other aspects of thisembodiment, a pharmaceutical composition comprises a mucolytic agent inan amount of, e.g., at most 0.1 mg/mL, at most 0.2 mg/mL, at most 0.3mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most 0.6 mg/mL, at most0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, at most 1 mg/mL, atmost 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most 5 mg/mL, at most6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9 mg/mL, at most 10mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13 mg/mL, at most 14mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17 mg/mL, at most 18mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21 mg/mL, at most 22mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25 mg/mL, at most 26mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29 mg/mL, or at most30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises a mucolytic agent in an amount of, e.g., about 0.1 mg/mL toabout 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL toabout 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL toabout 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL toabout 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL toabout 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL toabout 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL toabout 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL toabout 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL toabout 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL toabout 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL toabout 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL toabout 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL toabout 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL toabout 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL toabout 8 mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL toabout 10 mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75 mg/mL toabout 2 mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75 mg/mL toabout 4 mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75 mg/mL toabout 6 mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75 mg/mL toabout 8 mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75 mg/mL toabout 10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about10 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL,about 5 mg/mL to about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about5 mg/mL to about 20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10mg/mL to about 30 mg/mL.

A therapeutic compound disclosed herein may be an anti-histamine. Asused herein, the term “antihistamine” refers to a class of therapeuticcompounds that inhibits the action of histamine via one or morehistamine receptors. Typically, an anti-histamine blocking H1 receptorsis used to treat coughing, a cold, and/or an allergic reaction. Examplesof suitable antihistamines include, without limitation, Acrivastine,Alimemazine, Astemizole, Azatadine, Bromodiphenhydramine,Brompheniramine, Carbinoxamine, Cetirizine, Chlorpheniramine,Clemastine, Cyproheptadine, Desloratadine, Dexchlorpheniramine,Dextrobrompheniramine, Dimenhydrinate, Diphenhydramine, Doxylamine,Fexofenadine, Hydroxyzine, Levocetirizine, Loratadine, Meclizine,Mizolastine, Quetiapine, Pheniramine, Promethazine, Pyrilamine,Tripelennamine, and Triprolidine.

An antihistamine may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprises anantihistamine in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.25 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL,about 0.6 mg/mL, about 0.7 mg/mL, about 0.75 mg/mL, about 0.8 mg/mL,about 0.9 mg/mL, about 1 mg/mL, about 1.25 mg/mL, about 1.5 mg/mL, about1.75 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL,about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL,about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19mg/mL, about 20 mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL,about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28mg/mL, about 29 mg/mL, or about 30 mg/mL. In other aspects of thisembodiment, a pharmaceutical composition comprises an antihistamine inan amount of, e.g., at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, atleast 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9 mg/mL, at least 1mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8 mg/mL, at least 9mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least 12 mg/mL, at least13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, atleast 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL, at least 20 mg/mL,at least 21 mg/mL, at least 22 mg/mL, at least 23 mg/mL, at least 24mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least 27 mg/mL, at least28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL. In yet other aspectsof this embodiment, a pharmaceutical composition comprises anantihistamine in an amount of, e.g., at most 0.1 mg/mL, at most 0.2mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, atmost 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises an antihistamine in an amount of, e.g., about 0.1 mg/mL toabout 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL toabout 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL toabout 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL toabout 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL toabout 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL toabout 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL toabout 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL toabout 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL toabout 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL toabout 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL toabout 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL toabout 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL toabout 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL toabout 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL toabout 8 mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL toabout 10 mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75 mg/mL toabout 2 mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75 mg/mL toabout 4 mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75 mg/mL toabout 6 mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75 mg/mL toabout 8 mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75 mg/mL toabout 10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about10 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL,about 5 mg/mL to about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about5 mg/mL to about 20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10mg/mL to about 30 mg/mL.

A therapeutic compound disclosed herein may be a NSAID. As used herein,the term “NSAID” refers to a class of therapeutic compounds withanalgesic, anti-inflammatory, and anti-pyretic properties. NSAIDs reduceinflammation by blocking cyclooxygenase. NSAIDs may be classified basedon their chemical structure or mechanism of action. Non-limitingexamples of NSAIDs include a salicylate derivative NSAID, a p-aminophenol derivative NSAID, a propionic acid derivative NSAID, an aceticacid derivative NSAID, an enolic acid derivative NSAID, a fenamic acidderivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, aselective cyclooxygenase 1 (COX 1) inhibitor, and a selectivecyclooxygenase 2 (COX 2) inhibitor. A NSAID may be a profen. Examples ofa suitable salicylate derivative NSAID include, without limitation,Acetylsalicylic acid (asprin), Diflunisal, Hydroxylethyl Salicylate, andSalsalate. Examples of a suitable p-amino phenol derivative NSAIDinclude, without limitation, Paracetamol and Phenacetin. Examples of asuitable propionic acid derivative NSAID include, without limitation,Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen,Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin,Pranoprofen, And Suprofen. Examples Of A Suitable Acetic Acid DerivativeNSAID Include, Without Limitation, Aceclofenac, Acemetacin, Actarit,Alcofenac, Aloxipirin, Amfenac, Aminophenazone, Antraphenine,Azapropazone, Benorilate, Benzydamine, Butibufen, Chlorthenoxacine,Choline Salicylate, Clometacin, Diclofenac, Emorfazone, Epirizole,Etodolac, Feclobuzone, Felbinac, Fenbufen, Fenclofenac, Glafenine,Indometacin, Ketorolac, Lactyl Phenetidin, Metamizole, Metiazinic Acid,Mofebutazone, Mofezolac, Nabumetone, Nifenazone, Niflumic Acid,Oxametacin, Pipebuzone, Propyphenazone, Proquazone, Protozininc Acid,Salicylamide, Sulindac, Tiaramide, Tinoridine, And Zomepirac. Examplesof a suitable enolic acid (Oxicam) derivative NSAID include, withoutlimitation, Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, andTenoxicam. Examples of a suitable fenamic acid derivative NSAID include,without limitation, Flufenamic acid, Mefenamic acid, Meclofenamic acid,and Tolfenamic acid. Examples of a suitable selective COX-2 inhibitorsinclude, without limitation, Celecoxib, Etoricoxib, Firocoxib,Lumiracoxib, Meloxicam, Parecoxib, Rofecoxib, and Valdecoxib.

A NSAID may be in an amount suitable for its intended use. In aspects ofthis embodiment, a pharmaceutical composition comprises a NSAID in anamount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL,about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL,about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL,about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL,about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL, or about 30 mg/mLIn other aspects of this embodiment, a pharmaceutical compositioncomprises a NSAID in an amount of, e.g., about 10 mg/mL, about 20 mg/mL,about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 125 mg/mL,about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL,about 250 mg/mL, about 275 mg/mL, about 300 mg/mL, about 325 mg/mL,about 350 mg/mL, about 375 mg/mL, about 400 mg/mL, about 425 mg/mL,about 450 mg/mL, about 475 mg/mL, about 500 mg/mL, about 525 mg/mL,about 550 mg/mL, about 575 mg/mL, about 600 mg/mL, about 625 mg/mL,about 650 mg/mL, about 675 mg/mL, about 700 mg/mL, about 725 mg/mL,about 750 mg/mL, about 775 mg/mL, about 800 mg/mL, about 825 mg/mL,about 850 mg/mL, about 875 mg/mL, about 900 mg/mL, about 925 mg/mL,about 950 mg/mL, about 975 mg/mL, or about 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises a NSAID in an amount of, e.g., at least 0.1 mg/mL, at least0.2 mg/mL, at least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL,at least 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9mg/mL, at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4mg/mL, at least 5 mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8mg/mL, at least 9 mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least12 mg/mL, at least 13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, atleast 16 mg/mL, at least 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL,at least 20 mg/mL, at least 21 mg/mL, at least 22 mg/mL, at least 23mg/mL, at least 24 mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least27 mg/mL, at least 28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL Inaspects of this embodiment, a pharmaceutical composition comprises aNSAID in an amount of, e.g., at least 10 mg/mL, at least 20 mg/mL, atleast 30 mg/mL, at least 40 mg/mL, at least 50 mg/mL, at least 60 mg/mL,at least 70 mg/mL, at least 80 mg/mL, at least 90 mg/mL, at least 100mg/mL, at least 125 mg/mL, at least 150 mg/mL, at least 175 mg/mL, atleast 200 mg/mL, at least 225 mg/mL, at least 250 mg/mL, at least 275mg/mL, at least 300 mg/mL, at least 325 mg/mL, at least 350 mg/mL, atleast 375 mg/mL, at least 400 mg/mL, at least 425 mg/mL, at least 450mg/mL, at least 475 mg/mL, at least 500 mg/mL, at least 525 mg/mL, atleast 550 mg/mL, at least 575 mg/mL, at least 600 mg/mL, at least 625mg/mL, at least 650 mg/mL, at least 675 mg/mL, at least 700 mg/mL, atleast 725 mg/mL, at least 750 mg/mL, at least 775 mg/mL, at least 800mg/mL, at least 825 mg/mL, at least 850 mg/mL, at least 875 mg/mL, atleast 900 mg/mL, at least 925 mg/mL, at least 950 mg/mL, at least 975mg/mL, or at least 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises a NSAID in an amount of, e.g., at most 0.1 mg/mL, at most 0.2mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, atmost 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29mg/mL, or at most 30 mg/mL In yet other aspects of this embodiment, aNSAID is in an amount of, e.g., at most 10 mg/mL, at most 20 mg/mL, atmost 30 mg/mL, at most 40 mg/mL, at most 50 mg/mL, at most 60 mg/mL, atmost 70 mg/mL, at most 80 mg/mL, at most 90 mg/mL, at most 100 mg/mL, atmost 125 mg/mL, at most 150 mg/mL, at most 175 mg/mL, at most 200 mg/mL,at most 225 mg/mL, at most 250 mg/mL, at most 275 mg/mL, at most 300mg/mL, at most 325 mg/mL, at most 350 mg/mL, at most 375 mg/mL, at most400 mg/mL, at most 425 mg/mL, at most 450 mg/mL, at most 475 mg/mL, atmost 500 mg/mL, at most 525 mg/mL, at most 550 mg/mL, at most 575 mg/mL,at most 600 mg/mL, at most 625 mg/mL, at most 650 mg/mL, at most 675mg/mL, at most 700 mg/mL, at most 725 mg/mL, at most 750 mg/mL, at most775 mg/mL, at most 800 mg/mL, at most 825 mg/mL, at most 850 mg/mL, atmost 875 mg/mL, at most 900 mg/mL, at most 925 mg/mL, at most 950 mg/mL,at most 975 mg/mL, or at most 1000 mg/mL.

In other aspects of this embodiment, a pharmaceutical compositioncomprises a NSAID in an amount of, e.g., about 0.1 mg/mL to about 1mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL to about 3mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL to about 7mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL to about 9mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL to about 1mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL to about 3mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL to about 5mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL to about 7mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL to about 8mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL to about 10mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL to about 2mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL to about 4mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL to about 6mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL to about 8mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL to about 10mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 10 mg/mL,about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20 mg/mL, about1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL, about 1mg/mL to about 35 mg/mL, about 1 mg/mL to about 40 mg/mL, about 1 mg/mLto about 45 mg/mL, about 1 mg/mL to about 50 mg/mL, about 5 mg/mL toabout 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about 5 mg/mL to about20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL to about 30mg/mL, about 5 mg/mL to about 35 mg/mL, about 5 mg/mL to about 40 mg/mL,about 5 mg/mL to about 45 mg/mL, about 5 mg/mL to about 50 mg/mL, about10 mg/mL to about 20 mg/mL, about 10 mg/mL to about 30 mg/mL, about 10mg/mL to about 40 mg/mL, about 10 mg/mL to about 50 mg/mL, about 10mg/mL to about 60 mg/mL, about 10 mg/mL to about 70 mg/mL, about 10mg/mL to about 80 mg/mL, about 10 mg/mL to about 90 mg/mL, about 10mg/mL to about 100 mg/mL, about 25 mg/mL to about 50 mg/mL, about 25mg/mL to about 75 mg/mL, about 25 mg/mL to about 100 mg/mL, about 25mg/mL to about 125 mg/mL, about 25 mg/mL to about 150 mg/mL, about 25mg/mL to about 175 mg/mL, about 25 mg/mL to about 200 mg/mL, about 25mg/mL to about 225 mg/mL, about 25 mg/mL to about 250 mg/mL, about 50mg/mL to about 75 mg/mL, about 50 mg/mL to about 100 mg/mL, about 50mg/mL to about 125 mg/mL, about 50 mg/mL to about 150 mg/mL, about 50mg/mL to about 175 mg/mL, about 50 mg/mL to about 200 mg/mL, about 50mg/mL to about 225 mg/mL, about 50 mg/mL to about 250 mg/mL, about 50mg/mL to about 275 mg/mL, about 50 mg/mL to about 300 mg/mL, about 50mg/mL to about 325 mg/mL, about 50 mg/mL to about 350 mg/mL, about 50mg/mL to about 375 mg/mL, about 50 mg/mL to about 400 mg/mL, about 50mg/mL to about 425 mg/mL, about 50 mg/mL to about 450 mg/mL, about 50mg/mL to about 475 mg/mL, about 50 mg/mL to about 500 mg/mL, about 100mg/mL to about 150 mg/mL, about 100 mg/mL to about 200 mg/mL, about 100mg/mL to about 250 mg/mL, about 100 mg/mL to about 300 mg/mL, about 100mg/mL to about 350 mg/mL, about 100 mg/mL to about 400 mg/mL, about 100mg/mL to about 450 mg/mL, about 100 mg/mL to about 500 mg/mL, about 200mg/mL to about 300 mg/mL, about 200 mg/mL to about 400 mg/mL, about 200mg/mL to about 500 mg/mL, about 200 mg/mL to about 600 mg/mL, about 200mg/mL to about 700 mg/mL, about 200 mg/mL to about 800 mg/mL, about 200mg/mL to about 900 mg/mL, or about 200 mg/mL to about 1000 mg/mL.

A therapeutic compound disclosed herein may be a neuropathic pain agent.As used herein, the term “neuropathic pain agent” refers to a class oftherapeutic compounds with analgestic, antidepressant, anti-convulsant,anti-epileptic, and/or antispasmodic properties. Neuropathic pain agentsare typically, neurotransmitter inhibitors and/or ion channelinhibitors. Examples of suitable neuropathic pain agents include,without limitation, Acetazolamide, Amitriptyline, Amitriptylinoxide,Baclofen, Butriptyline, Carbamazepine, Carisoprodol, Clobazam,Clomipramine, Conotoxins, Cyclobenzaprine, Demexiptiline, Desipramine,Diazepam, Dibenzepin, Dimetacrine, Doxepin, Duloexetine, Ethotoin,Felbamate, Fosphenytoin, Gabapentin, Imipramine, Imipraminoxide,Ketamine, Lamotrigine, Lidocaine, Lignocaine, Lofepramine, Mephenytoin,Melitracen, Metapramine, Metaxalone, Methadone, Methocarbamol,Nitroxazepine, Nortriptyline, Noxiptiline, Oxcarbazepine, Phenobarbital,Phensuximide, Phenytoin, Pipofezine, Pregabalin, Progabide, Propizepine,Protriptyline, Quinupramine, Stiripentol, Tiagabine, Topiramate,Trimethadione, Valproate, Venlafaxine, Vigabatrin, and Zonisamide.

A neuropathic pain agent may be in an amount suitable for its intendeduse. In aspects of this embodiment, a pharmaceutical compositioncomprises a neuropathic pain agent in an amount of, e.g., about 0.1mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL,about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL,about 19 mg/mL, about 20 mg/mL, about 21 mg/mL, about 22 mg/mL, about 23mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL,about 28 mg/mL, about 29 mg/mL, or about 30 mg/mL. In other aspects ofthis embodiment, a pharmaceutical composition comprises a neuropathicpain agent in an amount of, e.g., at least 0.1 mg/mL, at least 0.2mg/mL, at least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL, atleast 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9mg/mL, at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4mg/mL, at least 5 mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8mg/mL, at least 9 mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least12 mg/mL, at least 13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, atleast 16 mg/mL, at least 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL,at least 20 mg/mL, at least 21 mg/mL, at least 22 mg/mL, at least 23mg/mL, at least 24 mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least27 mg/mL, at least 28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL. Inyet other aspects of this embodiment, a pharmaceutical compositioncomprises a neuropathic pain agent in an amount of, e.g., at most 0.1mg/mL, at most 0.2 mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most0.5 mg/mL, at most 0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, atmost 0.9 mg/mL, at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, atmost 4 mg/mL, at most 5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most8 mg/mL, at most 9 mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12mg/mL, at most 13 mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16mg/mL, at most 17 mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20mg/mL, at most 21 mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24mg/mL, at most 25 mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28mg/mL, at most 29 mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises a neuropathic pain agent in an amount of, e.g., about 0.1mg/mL to about 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1mg/mL to about 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1mg/mL to about 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1mg/mL to about 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25mg/mL to about 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25mg/mL to about 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25mg/mL to about 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25mg/mL to about 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25mg/mL to about 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5mg/mL to about 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5mg/mL to about 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5mg/mL to about 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5mg/mL to about 8 mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5mg/mL to about 10 mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75mg/mL to about 2 mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75mg/mL to about 4 mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75mg/mL to about 6 mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75mg/mL to about 8 mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75mg/mL to about 10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mLto about 10 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL toabout 20 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about30 mg/mL, about 5 mg/mL to about 10 mg/mL, about 5 mg/mL to about 15mg/mL, about 5 mg/mL to about 20 mg/mL, about 5 mg/mL to about 25 mg/mL,about 5 mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, orabout 10 mg/mL to about 30 mg/mL.

A therapeutic compound disclosed herein may be a terpene. As usedherein, the term “terpene” refers to a class of therapeutic compoundswith analgestic, anti-convulsant, and/or antispasmodic properties.Terpenes appear to function, in part, as a TripM8 calcium channelblocker involved in neurological signaling. A terpene is typically inthe form of an oil. Examples of suitable terpenes include, withoutlimitation, camphor oil, citronella, clove oil, eucalyptus oil, gingeroil, horsemint oil, I-menthol, lemon oil, limonene, marjoram oil, mintoil, neroli oil, peppermint oil, pine oil, rose oil, rosemary oil,spearmint oil, tea tree oil, thyme oil, and water mint oil.

A terpene may be in an amount suitable for its intended use. In aspectsof this embodiment, a pharmaceutical composition comprises a terpene inan amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL,about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL,about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL,about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL,about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL, or about 30mg/mL. In other aspects of this embodiment, a pharmaceutical compositioncomprises a terpene in an amount of, e.g., at least 0.1 mg/mL, at least0.2 mg/mL, at least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL,at least 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, at least 0.9mg/mL, at least 1 mg/mL, at least 2 mg/mL, at least 3 mg/mL, at least 4mg/mL, at least 5 mg/mL, at least 6 mg/mL, at least 7 mg/mL, at least 8mg/mL, at least 9 mg/mL, at least 10 mg/mL, at least 11 mg/mL, at least12 mg/mL, at least 13 mg/mL, at least 14 mg/mL, at least 15 mg/mL, atleast 16 mg/mL, at least 17 mg/mL, at least 18 mg/mL, at least 19 mg/mL,at least 20 mg/mL, at least 21 mg/mL, at least 22 mg/mL, at least 23mg/mL, at least 24 mg/mL, at least 25 mg/mL, at least 26 mg/mL, at least27 mg/mL, at least 28 mg/mL, at least 29 mg/mL, or at least 30 mg/mL. Inyet other aspects of this embodiment, a pharmaceutical compositioncomprises a terpene in an amount of, e.g., at most 0.1 mg/mL, at most0.2 mg/mL, at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, atmost 0.6 mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL,at most 1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, atmost 5 mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most9 mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most13 mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most17 mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most21 mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most25 mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most29 mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises a terpene in an amount of, e.g., about 0.1 mg/mL to about 1mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL to about 3mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL to about 5mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL to about 7mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL to about 9mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL to about 1mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL to about 3mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL to about 5mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL to about 7mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL to about 8mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL to about 10mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL to about 2mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL to about 4mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL to about 6mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL to about 8mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL to about 10mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75 mg/mL to about 2mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75 mg/mL to about 4mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75 mg/mL to about 6mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75 mg/mL to about 8mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75 mg/mL to about 10mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about 10 mg/mL,about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20 mg/mL, about1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL, about 5mg/mL to about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about 5 mg/mLto about 20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5 mg/mL toabout 30 mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10 mg/mL toabout 30 mg/mL.

A therapeutic compound disclosed herein may be an ACE inhibitor. ACEinhibitors reduce the activity of the renin-angiotensin-aldosteronesystem and are used primarily to treat hypertension, diabeticnephropathy, and congestive heart failure. However, one commonside-effect of ACE inhibitors is coughing. Thus, administration of amethylxanthine in conjunction with an ACE inhibitor would be a proactivemeasure to reduce or prevent the onset of a coughing side-effectproduced by the ACE inhibitor. Examples of suitable ACE inhibitorsinclude, without limitation, Captopril, Enalapril, Lisinopril, Meleate,and Ramipril.

An ACE inhibitor may be in an amount suitable for its intended use. Inaspects of this embodiment, a pharmaceutical composition comprises anACE inhibitor in an amount of, e.g., about 0.1 mg/mL, about 0.2 mg/mL,about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL,about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, or about 30 mg/mL. In other aspects of this embodiment, apharmaceutical composition comprises an ACE inhibitor in an amount of,e.g., at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3 mg/mL, atleast 0.4 mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, at least 0.7mg/mL, at least 0.8 mg/mL, at least 0.9 mg/mL, at least 1 mg/mL, atleast 2 mg/mL, at least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, atleast 6 mg/mL, at least 7 mg/mL, at least 8 mg/mL, at least 9 mg/mL, atleast 10 mg/mL, at least 11 mg/mL, at least 12 mg/mL, at least 13 mg/mL,at least 14 mg/mL, at least 15 mg/mL, at least 16 mg/mL, at least 17mg/mL, at least 18 mg/mL, at least 19 mg/mL, at least 20 mg/mL, at least21 mg/mL, at least 22 mg/mL, at least 23 mg/mL, at least 24 mg/mL, atleast 25 mg/mL, at least 26 mg/mL, at least 27 mg/mL, at least 28 mg/mL,at least 29 mg/mL, or at least 30 mg/mL. In yet other aspects of thisembodiment, a pharmaceutical composition comprises an ACE inhibitor inan amount of, e.g., at most 0.1 mg/mL, at most 0.2 mg/mL, at most 0.3mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most 0.6 mg/mL, at most0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, at most 1 mg/mL, atmost 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most 5 mg/mL, at most6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9 mg/mL, at most 10mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13 mg/mL, at most 14mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17 mg/mL, at most 18mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21 mg/mL, at most 22mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25 mg/mL, at most 26mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29 mg/mL, or at most30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises an ACE inhibitor in an amount of, e.g., about 0.1 mg/mL toabout 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL, about 0.1 mg/mL toabout 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL, about 0.1 mg/mL toabout 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL, about 0.1 mg/mL toabout 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL, about 0.1 mg/mL toabout 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL, about 0.25 mg/mL toabout 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL, about 0.25 mg/mL toabout 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL, about 0.25 mg/mL toabout 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL, about 0.25 mg/mL toabout 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL, about 0.25 mg/mL toabout 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL, about 0.25 mg/mL toabout 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.5 mg/mL toabout 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL, about 0.5 mg/mL toabout 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL, about 0.5 mg/mL toabout 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL, about 0.5 mg/mL toabout 8 mg/mL, about 0.5 mg/mL to about 9 mg/mL, about 0.5 mg/mL toabout 10 mg/mL, about 0.75 mg/mL to about 1 mg/mL, about 0.75 mg/mL toabout 2 mg/mL, about 0.75 mg/mL to about 3 mg/mL, about 0.75 mg/mL toabout 4 mg/mL, about 0.75 mg/mL to about 5 mg/mL, about 0.75 mg/mL toabout 6 mg/mL, about 0.75 mg/mL to about 7 mg/mL, about 0.75 mg/mL toabout 8 mg/mL, about 0.75 mg/mL to about 9 mg/mL, about 0.75 mg/mL toabout 10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 1 mg/mL to about10 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about 20mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about 30 mg/mL,about 5 mg/mL to about 10 mg/mL, about 5 mg/mL to about 15 mg/mL, about5 mg/mL to about 20 mg/mL, about 5 mg/mL to about 25 mg/mL, about 5mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, or about 10mg/mL to about 30 mg/mL.

A therapeutic compound disclosed herein may be an angiotensin IIreceptor antagonist. Angiotensin II receptor antagonist modulate theactivity of the renin-angiotensin-aldosterone system and are usedprimarily to treat hypertension, diabetic nephropathy, and congestiveheart failure. However, one common side-effect of angiotensin IIreceptor antagonists is coughing. Thus, administration of amethylxanthine in conjunction with an angiotensin II receptor antagonistwould be a proactive measure to reduce or prevent the onset of acoughing side-effect produced by the angiotensin II receptor antagonist.Examples of suitable angiotensin II receptor antagonists include,without limitation, Azilsartan, Candesartan, Eprosartan, Irbesartan,Losartan, Olmesartan, Telmisartan, and Valsartan.

An angiotensin II receptor antagonist may be in an amount suitable forits intended use. In aspects of this embodiment, a pharmaceuticalcomposition comprises an angiotensin II receptor antagonist in an amountof, e.g., about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL,about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL,about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL,about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL, or about 30mg/mL. In other aspects of this embodiment, a pharmaceutical compositioncomprises an angiotensin II receptor antagonist in an amount of, e.g.,at least 0.1 mg/mL, at least 0.2 mg/mL, at least 0.3 mg/mL, at least 0.4mg/mL, at least 0.5 mg/mL, at least 0.6 mg/mL, at least 0.7 mg/mL, atleast 0.8 mg/mL, at least 0.9 mg/mL, at least 1 mg/mL, at least 2 mg/mL,at least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, at least 6 mg/mL,at least 7 mg/mL, at least 8 mg/mL, at least 9 mg/mL, at least 10 mg/mL,at least 11 mg/mL, at least 12 mg/mL, at least 13 mg/mL, at least 14mg/mL, at least 15 mg/mL, at least 16 mg/mL, at least 17 mg/mL, at least18 mg/mL, at least 19 mg/mL, at least 20 mg/mL, at least 21 mg/mL, atleast 22 mg/mL, at least 23 mg/mL, at least 24 mg/mL, at least 25 mg/mL,at least 26 mg/mL, at least 27 mg/mL, at least 28 mg/mL, at least 29mg/mL, or at least 30 mg/mL. In yet other aspects of this embodiment, apharmaceutical composition comprises an angiotensin II receptorantagonist in an amount of, e.g., at most 0.1 mg/mL, at most 0.2 mg/mL,at most 0.3 mg/mL, at most 0.4 mg/mL, at most 0.5 mg/mL, at most 0.6mg/mL, at most 0.7 mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, at most1 mg/mL, at most 2 mg/mL, at most 3 mg/mL, at most 4 mg/mL, at most 5mg/mL, at most 6 mg/mL, at most 7 mg/mL, at most 8 mg/mL, at most 9mg/mL, at most 10 mg/mL, at most 11 mg/mL, at most 12 mg/mL, at most 13mg/mL, at most 14 mg/mL, at most 15 mg/mL, at most 16 mg/mL, at most 17mg/mL, at most 18 mg/mL, at most 19 mg/mL, at most 20 mg/mL, at most 21mg/mL, at most 22 mg/mL, at most 23 mg/mL, at most 24 mg/mL, at most 25mg/mL, at most 26 mg/mL, at most 27 mg/mL, at most 28 mg/mL, at most 29mg/mL, or at most 30 mg/mL

In yet other aspects of this embodiment, a pharmaceutical compositioncomprises an angiotensin II receptor antagonist in an amount of, e.g.,about 0.1 mg/mL to about 1 mg/mL, about 0.1 mg/mL to about 2 mg/mL,about 0.1 mg/mL to about 3 mg/mL, about 0.1 mg/mL to about 4 mg/mL,about 0.1 mg/mL to about 5 mg/mL, about 0.1 mg/mL to about 6 mg/mL,about 0.1 mg/mL to about 7 mg/mL, about 0.1 mg/mL to about 8 mg/mL,about 0.1 mg/mL to about 9 mg/mL, about 0.1 mg/mL to about 10 mg/mL,about 0.25 mg/mL to about 1 mg/mL, about 0.25 mg/mL to about 2 mg/mL,about 0.25 mg/mL to about 3 mg/mL, about 0.25 mg/mL to about 4 mg/mL,about 0.25 mg/mL to about 5 mg/mL, about 0.25 mg/mL to about 6 mg/mL,about 0.25 mg/mL to about 7 mg/mL, about 0.25 mg/mL to about 7.5 mg/mL,about 0.25 mg/mL to about 8 mg/mL, about 0.25 mg/mL to about 9 mg/mL,about 0.25 mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 1 mg/mL,about 0.5 mg/mL to about 2 mg/mL, about 0.5 mg/mL to about 3 mg/mL,about 0.5 mg/mL to about 4 mg/mL, about 0.5 mg/mL to about 5 mg/mL,about 0.5 mg/mL to about 6 mg/mL, about 0.5 mg/mL to about 7 mg/mL,about 0.5 mg/mL to about 8 mg/mL, about 0.5 mg/mL to about 9 mg/mL,about 0.5 mg/mL to about 10 mg/mL, about 0.75 mg/mL to about 1 mg/mL,about 0.75 mg/mL to about 2 mg/mL, about 0.75 mg/mL to about 3 mg/mL,about 0.75 mg/mL to about 4 mg/mL, about 0.75 mg/mL to about 5 mg/mL,about 0.75 mg/mL to about 6 mg/mL, about 0.75 mg/mL to about 7 mg/mL,about 0.75 mg/mL to about 8 mg/mL, about 0.75 mg/mL to about 9 mg/mL,about 0.75 mg/mL to about 10 mg/mL, about 1 mg/mL to about 5 mg/mL,about 1 mg/mL to about 10 mg/mL, about 1 mg/mL to about 15 mg/mL, about1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1mg/mL to about 30 mg/mL, about 5 mg/mL to about 10 mg/mL, about 5 mg/mLto about 15 mg/mL, about 5 mg/mL to about 20 mg/mL, about 5 mg/mL toabout 25 mg/mL, about 5 mg/mL to about 30 mg/mL, about 10 mg/mL to about20 mg/mL, or about 10 mg/mL to about 30 mg/mL.

A pharmaceutical composition disclosed herein may optionally include apharmaceutically-acceptable carrier that facilitates processing of anactive ingredient into pharmaceutically-acceptable compositions. As usedherein, the term “pharmacologically-acceptable carrier” is synonymouswith “pharmacological carrier” and means any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary or excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active ingredients can besoluble or can be delivered as a suspension in the desired carrier ordiluent. Any of a variety of pharmaceutically acceptable carriers can beused including, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like;solvents; dispersion media; coatings; antibacterial and antifungalagents; isotonic and absorption delaying agents; or any other inactiveingredient. Selection of a pharmacologically acceptable carrier candepend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activeingredient, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins,20th ed. 2000); Goodman & Gilman's The Pharmacological Basis ofTherapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4th edition 2003). These protocols areroutine procedures and any modifications are well within the scope ofone skilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, flavoring agents,coloring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, citratebuffers, phosphate buffers, neutral buffered saline, phosphate bufferedsaline and borate buffers. It is understood that acids or bases can beused to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition and chelants, such as, e.g., DTPA orDTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustorsuseful in a pharmaceutical composition include, without limitation,salts such as, e.g., sodium chloride, potassium chloride, mannitol orglycerin and other pharmaceutically acceptable tonicity adjustor. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be formulated for either local orsystemic delivery using topical, enteral or parenteral routes ofadministration. Additionally, a therapeutic compound disclosed hereinmay be formulated by itself in a pharmaceutical composition, or may beformulated together with one or more other therapeutic compoundsdisclosed herein in a single pharmaceutical composition.

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into an inhaled formulation.Inhaled formulations suitable for enteral or parenteral administrationinclude, without limitation, aerosols, dry powders. A therapeuticcompound or composition disclosed herein intended for suchadministration may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions.

In such inhaled dosage forms, the therapeutic compound may be preparedfor delivery as an aerosol in a liquid propellant for use in apressurised (PDI) or other metered dose inhaler (MDI). Propellantssuitable for use in a PDI or MDI include, without limitation, CFC-12,HFA-134a, HFA-227, HCFC-22 (difluorochloromethane), HFA-152(difluoroethane and isobutane). A therapeutic compound may also bedelivered using a nebulisers or other aerosol delivery system. Atherapeutic compound may be prepared for delivery as a dry powder foruse in a dry powder inhaler (DPI). A dry powder for use in the inhalerswill usually have a mass median aerodynamic diameter of less than 30 pm,preferably less than 20 pm and more preferably less than 10 pm.Microparticles having aerodynamic diameters in the range of about 5 pmto about 0.5 pm will generally be deposited in the respiratorybronchioles, whereas smaller particles, having aerodynamic diameters inthe range of about 2 pm to about 0.05 pm, are likely to be deposited inthe alveoli. A DPI may be a passive delivery mechanism, which relies onthe individual's inspiration to introduce the particles into the lungs,or an active delivery mechanism, requiring a mechanism for deliveringthe powder to the individual. As disclosed herein, an equivalentantitussive effect for inhaled methylxanthine requires only one-thirdthe dose of the same methylxanthine administered orally. In inhalatoryformulations, a therapeutically effective amount of a therapeuticcompound disclosed herein for an inhaled formulation may be betweenabout 0.0001% (w/v) to about 60% (w/v), about 0.001% (w/v) to about40.0% (w/v), or about 0.01% (w/v) to about 20.0% (w/v). In inhalatoryformulations, a therapeutically effective amount of a therapeuticcompound disclosed herein for an inhaled formulation may also be betweenabout 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to about40.0% (w/w), or about 0.01% (w/w) to about 20.0% (w/w).

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into a solid formulation. Solidformulations suitable for enteral or parenteral administration include,without limitation, capsules, tablets, pills, troches, lozenges, powdersand granules suitable for inhalation or for reconstitution into sterileinjectable solutions or dispersions. A therapeutic compound orcomposition disclosed herein intended for such administration may beprepared according to any method known to the art for the manufacture ofpharmaceutical compositions. In such solid dosage forms, the therapeuticcompound may be admixed with (a) at least one inert customary excipient(or carrier), such as, e.g., sodium citrate or dicalcium phosphate or(b) fillers or extenders, as for example, starch, lactose, sucrose,glucose, mannitol, isomalt, and silicic acid, (c) binders, such as,e.g., carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose and acacia, (d) humectants, such as, e.g., glycerol, (e)disintegrating agents, such as, e.g., agar-agar, calcium carbonate, cornstarch, potato starch, tapioca starch, alginic acid, certain complexsilicates and sodium carbonate, (0 solution retarders, such as, e.g.,paraffin, (g) absorption accelerators, such as, e.g., quaternaryammonium compounds, (h) wetting agents, such as, e.g., cetyl alcohol andglycerol monostearate, (i) adsorbents, such as, e.g., kaolin andbentonite, (j) lubricants, such as, e.g., talc, stearic acid, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate or mixtures thereof, and (k) buffering agents. The tablets maybe uncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. In solid formulations, a therapeutically effective amountof a therapeutic compound disclosed herein typically may be betweenabout 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to about40.0% (w/w), or about 0.01% (w/w) to about 20.0% (w/w).

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into a semi-solid formulation.Semi-solid formulations suitable for topical administration include,without limitation, ointments, creams, salves, and gels. A therapeuticcompound or composition disclosed herein intended for suchadministration may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions. In semi-solidformulations, a therapeutically effective amount of a therapeuticcompound disclosed herein typically may be between about 0.0001% (w/v)to about 60% (w/v), about 0.001% (w/v) to about 40.0% (w/v), or about0.01% (w/v) to about 20.0% (w/v). In semi-solid formulations, atherapeutically effective amount of a therapeutic compound disclosedherein typically may also be between about 0.0001% (w/w) to about 60%(w/w), about 0.001% (w/w) to about 40.0% (w/w), or about 0.01% (w/w) toabout 20.0% (w/w).

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into a liquid formulation.Liquid formulations suitable for enteral or parenteral administrationinclude, without limitation, solutions, syrups, elixirs, dispersions,emulsions, and suspensions. A therapeutic compound or compositiondisclosed herein intended for such administration may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions. In such liquid dosage forms, a therapeuticcompound or composition disclosed herein may be admixed with (a)suitable aqueous and nonaqueous carriers, (b) diluents, (c) solvents,such as, e.g., water, ethanol, propylene glycol, polyethyleneglycol,glycerol, vegetable oils, such as, e.g., rapeseed oil and olive oil, andinjectable organic esters such as ethyl oleate; and/or fluidity agents,such as, e.g., surfactants or coating agents like lecithin. In the caseof dispersions and suspensions, fluidity can also be controlled bymaintaining a particular particle size. In liquid formulations, atherapeutically effective amount of a therapeutic compound disclosedherein typically may be between about 0.0001% (w/v) to about 60% (w/v),about 0.001% (w/v) to about 40.0% (w/v), or about 0.01% (w/v) to about20.0% (w/v).

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring agents, and coloringagents.

Liquid suspensions may be formulated by suspending a therapeuticcompound disclosed herein in admixture with excipients suitable for themanufacture of aqueous suspensions. Such excipients are suspendingagents, for example sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, pectin, polyvinylpyrrolidone, polyvinyl alcohol, natural gum, agar, gum tragacanth andgum acacia; dispersing or wetting agents may be a naturally occurringphosphatide, for example lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long-chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acids,for example polyoxyethylene sorbitan monooleate.

Oily suspensions may be formulated by suspending a therapeutic compounddisclosed herein in admixture with (a) vegetable oils, such as, e.g.,almond oil, arachis oil, avocado oil, canola oil, castor oil, coconutoil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil,linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice branoil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil,walnut oil, wheat germ oil, or a combination thereof, (b) a saturatedfatty acid, an unsaturated fatty acid, or a combination thereof, suchas, e.g., palmitic acid, stearic acid, oleic acid, linoleic acid,linolenic acid, or a combination thereof, (c) mineral oil such as, e.g.,liquid paraffin, (d) surfactants or detergents. The oily suspensions maycontain a thickening agent, for example beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the combined therapeuticcompounds in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives.

A therapeutic compound disclosed herein may be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil asdisclosed herein or a mineral oil as disclosed herein or mixturesthereof. Suitable emulsifying agents may be naturally occurring gums,such as, e.g., gum acacia or gum tragacanth, naturally occurringphosphatidyl, for example soya bean, lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate and condensation products of the said partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monooleate.

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may also be incorporated into a drugdelivery platform in order to achieve a controlled release profile overtime. Such a drug delivery platform comprises a therapeutic compounddisclosed herein dispersed within a polymer matrix, typically abiodegradable, bioerodible, and/or bioresorbable polymer matrix. As usedherein, the term “polymer” refers to synthetic homo- or copolymers,naturally occurring homo- or copolymers, as well as syntheticmodifications or derivatives thereof having a linear, branched or starstructure. Copolymers can be arranged in any form, such as, e.g.,random, block, segmented, tapered blocks, graft, or triblock. Polymersare generally condensation polymers. Polymers can be further modified toenhance their mechanical or degradation properties by introducingcross-linking agents or changing the hydrophobicity of the sideresidues. If crosslinked, polymers are usually less than 5% crosslinked,usually less than 1% crosslinked.

Suitable polymers include, without limitation, alginates, aliphaticpolyesters, polyalkylene oxalates, polyamides, polyamidoesters,polyanhydrides, polycarbonates, polyesters, polyethylene glycol,polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters,polypeptides, polyphosphazenes, polysaccharides, and polyurethanes. Thepolymer usually comprises at least about 10% (w/w), at least about 20%(w/w), at least about 30% (w/w), at least about 40% (w/w), at leastabout 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), atleast about 80% (w/w), or at least about 90% (w/w) of the drug deliveryplatform. Examples of biodegradable, bioerodible, and/or bioresorbablepolymers and methods useful to make a drug delivery platform aredescribed in, e.g., Drost, et. al., Controlled Release Formulation, U.S.Pat. No. 4,756,911; Smith, et. al., Sustained Release Drug DeliveryDevices, U.S. Pat. No. 5,378,475; Wong and Kochinke, Formulation forControlled Release of Drugs by Combining Hyrophilic and HydrophobicAgents, U.S. Pat. No. 7,048,946; Hughes, et. al., Compositions andMethods for Localized Therapy of the Eye, U.S. Patent Publication2005/0181017; Hughes, Hypotensive Lipid-Containing BiodegradableIntraocular Implants and Related Methods, U.S. Patent Publication2005/0244464; Altman, et al., Silk Fibroin Hydrogels and Uses Thereof,U.S. Patent Publication 2011/0008437; each of which is incorporated byreference in its entirety.

In aspects of this embodiment, a polymer composing the matrix is apolypeptide such as, e.g., silk fibroin, keratin, or collagen. In otheraspects of this embodiment, a polymer composing the matrix is apolysaccharide such as, e.g., cellulose, agarose, elastin, chitosan,chitin, or a glycosaminoglycan like chondroitin sulfate, dermatansulfate, keratan sulfate, or hyaluronic acid. In yet other aspects ofthis embodiment, a polymer composing the matrix is a polyester such as,e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,caprolactone, and combinations thereof.

One of ordinary skill in the art appreciates that the selection of asuitable polymer for forming a suitable disclosed drug delivery platformdepends on several factors. The more relevant factors in the selectionof the appropriate polymer(s), include, without limitation,compatibility of polymer with drug, desired release kinetics of drug,desired biodegradation kinetics of platform at implantation site,desired bioerodible kinetics of platform at implantation site, desiredbioresorbable kinetics of platform at implantation site, in vivomechanical performance of platform, processing temperatures,biocompatibility of platform, and patient tolerance. Other relevantfactors that, to some extent, dictate the in vitro and in vivo behaviorof the polymer include the chemical composition, spatial distribution ofthe constituents, the molecular weight of the polymer and the degree ofcrystallinity.

A drug delivery platform includes both a sustained release drug deliveryplatform and an extended release drug delivery platform. As used herein,the term “sustained release” refers to the release of a therapeuticcompound disclosed herein over a period of about seven days or more. Asused herein, the term “extended release” refers to the release of atherapeutic compound disclosed herein over a period of time of less thanabout seven days.

In aspects of this embodiment, a sustained release drug deliveryplatform releases a therapeutic compound disclosed herein withsubstantially zero order release kinetics over a period of, e.g., about7 days after administration, about 15 days after administration, about30 days after administration, about 45 days after administration, about60 days after administration, about 75 days after administration, orabout 90 days after administration. In other aspects of this embodiment,a sustained release drug delivery platform releases a therapeuticcompound disclosed herein with substantially zero order release kineticsover a period of, e.g., at least 7 days after administration, at least15 days after administration, at least 30 days after administration, atleast 45 days after administration, at least 60 days afteradministration, at least 75 days after administration, or at least 90days after administration.

In aspects of this embodiment, a sustained release drug deliveryplatform releases a therapeutic compound disclosed herein withsubstantially first order release kinetics over a period of, e.g., about7 days after administration, about 15 days after administration, about30 days after administration, about 45 days after administration, about60 days after administration, about 75 days after administration, orabout 90 days after administration. In other aspects of this embodiment,a sustained release drug delivery platform releases a therapeuticcompound disclosed herein with substantially first order releasekinetics over a period of, e.g., at least 7 days after administration,at least 15 days after administration, at least 30 days afteradministration, at least 45 days after administration, at least 60 daysafter administration, at least 75 days after administration, or at least90 days after administration.

In aspects of this embodiment, a drug delivery platform releases atherapeutic compound disclosed herein with substantially zero orderrelease kinetics over a period of, e.g., about 1 day afteradministration, about 2 days after administration, about 3 days afteradministration, about 4 days after administration, about 5 days afteradministration, or about 6 days after administration. In other aspectsof this embodiment, a drug delivery platform releases a therapeuticcompound disclosed herein with substantially zero order release kineticsover a period of, e.g., at most 1 day after administration, at most 2days after administration, at most 3 days after administration, at most4 days after administration, at most 5 days after administration, or atmost 6 days after administration.

In aspects of this embodiment, a drug delivery platform releases atherapeutic compound disclosed herein with substantially first orderrelease kinetics over a period of, e.g., about 1 day afteradministration, about 2 days after administration, about 3 days afteradministration, about 4 days after administration, about 5 days afteradministration, or about 6 days after administration. In other aspectsof this embodiment, a drug delivery platform releases a therapeuticcompound disclosed herein with substantially first order releasekinetics over a period of, e.g., at most 1 day after administration, atmost 2 days after administration, at most 3 days after administration,at most 4 days after administration, at most 5 days afteradministration, or at most 6 days after administration.

Aspects of the present specification disclose, in part, a method oftreating an individual with a coughing condition. In one embodiment, themethod comprises the step of administering to an individual in needthereof a pharmaceutical composition disclosed herein, whereinadministration reduces a symptom associated with the coughing condition,thereby treating the individual.

A coughing condition refers to a vagal nerve-based disorder where anindividual has a sudden reflex (the cough reflex), which may occurrepetitively, physiologically designed to clear the large breathingpassages from any of various irritants, particles, microbes or otherorganisms, secretions, etc., and which is usually accompanied by adistinctive sound. A cough comprises an inhalation, a forced exhalationagainst a closed glottis, and a release of air from the lungs whichimmediately follows opening of the glottis. The cough reflex isinitiated by stimulating two types of afferent nerves, the myelinatedrapidly adapting receptors and the nonmyelinated C-fibers with endingsin the lungs.

A cough can be classified by its duration, character, quality, andtiming. For example, a cough may be classified as an acute cough, asubacute cough, or a chronic cough. An acute cough is one where there isa sudden onset of a cough and such coughing is present in an individualfor three weeks or less. A subacute cough is one where the coughing ispresent in an individual for between about three weeks to about eightweeks. A chronic cough is one where the coughing is present in anindividual for about eight weeks or more.

A cough may also be classified as a non-productive (dry) cough or aproductive cough. A non-productive cough is one where no phlegm orsputum is expelled from the respiratory system during a cough. Aproductive cough is one where no phlegm or sputum is expelled from therespiratory system during a cough. A cough may also be classified basedon occurrence such as when occurring only at night, occurring duringboth night and day, or occurring during the day only.

A cough can initially be brought on by many factors, including withoutlimitation, asthma; bronchitis; aspiration or choking; gastroesophagealreflux disease (GERD); infection of the respiratory tract by bacteria,viruses, or other parasites; inflammation; some medications, such as,e.g., ACE inhibitors; pollution; post-nasal drip; smoking; vagal nerveirritation; diseases of the external auditory canal; lung disease, suchas bronchiectasis, cystic fibrosis, interstitial lung disease andsarcoidosis; tumors or other cancer in the lungs; habit (habit cough); atic or other disorders such as Tourette syndrome (tic cough); and,cardiovascular diseases such as heart failure, pulmonary infarction andaortic aneurysm.

Where a cough is the result of an infection of the respiratory tract,some such infections include without limitation a cold, croup,pertussis, pneumonia, and tuberculosis. Asthma is a common cause ofchronic cough. Where a cough is the only symptom of the asthma (besidesbronchial hyperresponsiveness and reversibility), the asthma is termedcough-variant asthma. Atopic cough is a cough which occurs inindividuals who have a family history of allergic hypersensitivity(atopy) and a high number of eosinophils in the sputum, but normalairway function. A psychogenic cough may arise without a physicalinitiating factor, potentially due to emotional or psychological issues.A post-infectious cough, as used herein, refers to a cough that persistsafter the infection or other factor that initially brought on the coughhas cleared. A post-infectious cough is typically is a non-productivecough accompanied by a ticklish feeling in the lungs, chest or throat,and can persist for weeks after removal of the initiating factor. Theactual cause of the post-infectious cough may be inflammation due to theinitiating factor, which in turn produces discomfort or the ticklishfeeling, which produces more coughing. Ironically then, thepost-infectious cough itself serves as the cause of the cough.

Aspects of the present specification disclose, in part, treating anindividual suffering from a coughing condition. As used herein, the term“treating,” refers to reducing or eliminating in an individual aclinical symptom of a coughing condition; or delaying or preventing inan individual the onset of a clinical symptom of a coughing condition.For example, the term “treating” can mean reducing a symptom of acondition characterized by a coughing condition by, e.g., at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90% at least 95%, or atleast 100%. As another example, the term “treating” can mean controllinga cough such as, e.g., reducing the number of coughs per given timeperiod and/or the severity of cough. The actual symptoms associated witha coughing condition are well known and can be determined by a person ofordinary skill in the art by taking into account factors, including,without limitation, the location of the coughing condition, the cause ofthe coughing condition, the severity of the coughing condition, and/orthe tissue or organ affected by the coughing condition. Those of skillin the art will know the appropriate symptoms or indicators associatedwith a specific type of coughing condition and will know how todetermine if an individual is a candidate for treatment as disclosedherein.

Coughing condition symptoms include, without limitation, coughing,hoarseness, sore throat, breathing difficulty, respiratory congestion,respiratory constriction, respiratory inflammation, phlegm production,fainting, insomnia, vomiting, subconjunctival hemorrhage (red eye),cough defecation, cough urination, abdominal hernia, pelvic hernia,costochondritis, and lower rib fractures. The actual symptoms associatedwith a coughing condition are well known and can be determined by aperson of ordinary skill in the art by taking into account factors,including, without limitation, the location of the coughing condition,the cause of the coughing condition, the severity of the coughingcondition, the tissue or organ affected by the coughing condition.

In one embodiment, a coughing condition comprises an acute coughingcondition.

In another embodiment, a coughing condition comprises a subacutecoughing condition.

In another embodiment, a coughing condition comprises a chronic coughingcondition.

In another embodiment, a coughing condition comprises a non-productivecoughing condition.

In another embodiment, a coughing condition comprises a productivecoughing condition.

In another embodiment, a coughing condition comprises a cough associatedwith a disease or disorder. In aspects of this embodiment, the diseaseor disorder includes an asthma, an atopic cough a bronchitis, agastroesophageal reflux disease (GERD), an infection of the respiratorytract, an inflammation, a medication, a pollutant, a post-nasal drip, asmoking event, a vagal nerve irritation, a diseases of the externalauditory canal, a lung disease, a lung tumor, a habit cough, a tic, aTourette syndrome, a cardiovascular disease, a post-infectious cough. Inan aspect of this embodiment, the lung disease includes, withoutlimitation, a bronchiectasis, a cystic fibrosis, an interstitial lungdisease, a sarcoidosis, a COPD. In another aspect of this embodiment,the cardiovascular disease includes, without limitation, a heartfailure, a pulmonary infarction and an aortic aneurysm. In yet anotheraspect of this embodiment, the infection of the respiratory tractincludes, without limitation, a cold, croup, pertussis, pneumonia, andtuberculosis.

A composition or compound is administered to an individual. Anindividual is typically a human being. Typically, any individual who isa candidate for a conventional coughing condition treatment is acandidate for a coughing condition treatment disclosed herein.Pre-operative evaluation typically includes routine history and physicalexamination in addition to thorough informed consent disclosing allrelevant risks and benefits of the procedure.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in a therapeutically effective amount. As used herein, the term“effective amount” is synonymous with “therapeutically effectiveamount”, “effective dose”, or “therapeutically effective dose” and whenused in reference to treating a coughing condition refers to the minimumdose of a therapeutic compound disclosed herein necessary to achieve thedesired therapeutic effect and includes a dose sufficient to reduce asymptom associated with a coughing condition. The effectiveness of atherapeutic compound disclosed herein in treating a coughing conditioncan be determined by observing an improvement in an individual basedupon one or more clinical symptoms, and/or physiological indicatorsassociated with the coughing condition. An improvement in a coughingcondition also can be indicated by a reduced need for a concurrenttherapy.

The appropriate effective amount of a therapeutic compound disclosedherein to be administered to an individual for a particular coughingcondition can be determined by a person of ordinary skill in the art bytaking into account factors, including, without limitation, the type ofcoughing condition, the location of the coughing condition, the cause ofthe coughing condition, the severity of the coughing condition, thedegree of relief desired, the duration of relief desired, the particulartherapeutic compound used, the rate of excretion of the therapeuticcompound used, the pharmacodynamics of the therapeutic compound used,the nature of the other compounds to be included in the composition, theparticular route of administration, the particular characteristics,history and risk factors of the patient, such as, e.g., age, weight,general health and the like, or any combination thereof. Additionally,where repeated administration of a therapeutic compound is used, aneffective amount of a therapeutic compound will further depend uponfactors, including, without limitation, the frequency of administration,the half-life of the therapeutic compound, or any combination thereof.In is known by a person of ordinary skill in the art that an effectiveamount of a therapeutic compound disclosed herein can be extrapolatedfrom in vitro assays and in vivo administration studies using animalmodels prior to administration to humans.

Wide variations in the necessary effective amount are to be expected inview of the differing efficiencies of the various routes ofadministration. For instance, oral administration of a therapeuticcompound disclosed herein generally would be expected to require higherdosage levels than administration by inhalation. Similarly, systemicadministration of a therapeutic compound disclosed herein would beexpected to require higher dosage levels than a local administration.Variations in these dosage levels can be adjusted using standardempirical routines of optimization, which are well-known to a person ofordinary skill in the art. The precise therapeutically effective dosagelevels and patterns are preferably determined by the attending physicianin consideration of the above-identified factors. One skilled in the artwill recognize that the condition of the individual can be monitoredthroughout the course of therapy and that the effective amount of atherapeutic compound disclosed herein that is administered can beadjusted accordingly.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein reduces a symptom associated witha coughing condition by, e.g., at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95% or atleast 100%. In other aspects of this embodiment, a therapeuticallyeffective amount of a therapeutic compound disclosed herein reduces asymptom associated with a coughing condition by, e.g., at most 10%, atmost 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, atmost 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most95% or at most 100%. In yet other aspects of this embodiment, atherapeutically effective amount of a therapeutic compound disclosedherein reduces a symptom associated with a coughing condition by, e.g.,about 10% to about 100%, about 10% to about 90%, about 10% to about 80%,about 10% to about 70%, about 10% to about 60%, about 10% to about 50%,about 10% to about 40%, about 20% to about 100%, about 20% to about 90%,about 20% to about 80%, about 20% to about 20%, about 20% to about 60%,about 20% to about 50%, about 20% to about 40%, about 30% to about 100%,about 30% to about 90%, about 30% to about 80%, about 30% to about 70%,about 30% to about 60%, or about 30% to about 50%.

In other aspects of this embodiment, a therapeutically effective amountof a therapeutic compound disclosed herein generally is in the range ofabout 0. 001 mg/kg/day to about 100 mg/kg/day. In aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day,at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day,at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, atleast 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, atleast 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. Inother aspects of this embodiment, an effective amount of a therapeuticcompound disclosed herein may be in the range of, e.g., about 0.001mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100mg/kg/day. In yet other aspects of this embodiment, an effective amountof a therapeutic compound disclosed herein may be in the range of, e.g.,about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day toabout 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100mg/kg/day. In still other aspects of this embodiment, an effectiveamount of a therapeutic compound disclosed herein may be in the rangeof, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/dayto about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be in the range of, e.g.,about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be in the range of, e.g., about 5 mg/kg/day to about 10mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day toabout 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day toabout 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, a therapeutically effective amountof a therapeutic compound disclosed herein generally is in the range ofabout 1 mg/day to about 3,000 mg/day. In aspects of this embodiment, aneffective amount of a therapeutic compound disclosed herein may be,e.g., at least 40 mg/day, at least 50 mg/day, at least 60 mg/day, atleast 70 mg/day, at least 80 mg/day, at least 90 mg/day, at least 100mg/day, at least 110 mg/day, at least 120 mg/day, at least 130 mg/day,at least 140 mg/day, at least 150 mg/day, at least 160 mg/day, at least170 mg/day, at least 180 mg/day, at least 190 mg/day, at least 200mg/day, at least 210 mg/day, at least 220 mg/day, at least 230 mg/day,at least 240 mg/day, at least 250 mg/day, at least 300 mg/day, at least350 mg/day, at least 400 mg/day, at least 450 mg/day, at least 500mg/day, at least 550 mg/day, at least 600 mg/day, at least 650 mg/day,at least 700 mg/day, at least 750 mg/day, at least 800 mg/day, at least850 mg/day, at least 900 mg/day, at least 950 mg/day, at least 1,000mg/day, at least 1,50 mg/day, at least 1,100 mg/day, at least 1,150mg/day, at least 1,200 mg/day, at least 1,250 mg/day, at least 1,300mg/day, at least 1,350 mg/day, at least 1,400 mg/day, at least 1,450mg/day, at least 1,500 mg/day, at least 1,600 mg/day, at least 1,700mg/day, at least 1,800 mg/day, at least 1,900 mg/day, at least 2,000mg/day, at least 2,100 mg/day, at least 2,200 mg/day, at least 2,300mg/day, at least 2,400 mg/day, at least 2,500 mg/day, at least 2,600mg/day, at least 2,700 mg/day, at least 2,800 mg/day, at least 2,900mg/day, or at least 3,000 mg/day. In yet aspects of this embodiment, aneffective amount of a therapeutic compound disclosed herein may be,e.g., at most 40 mg/day, at most 50 mg/day, at most 60 mg/day, at most70 mg/day, at most 80 mg/day, at most 90 mg/day, at most 100 mg/day, atmost 110 mg/day, at most 120 mg/day, at most 130 mg/day, at most 140mg/day, at most 150 mg/day, at most 160 mg/day, at most 170 mg/day, atmost 180 mg/day, at most 190 mg/day, at most 200 mg/day, at most 210mg/day, at most 220 mg/day, at most 230 mg/day, at most 240 mg/day, atmost 250 mg/day, at most 300 mg/day, at most 350 mg/day, at most 400mg/day, at most 450 mg/day, at most 500 mg/day, at most 550 mg/day, atmost 600 mg/day, at most 650 mg/day, at most 700 mg/day, at most 750mg/day, at most 800 mg/day, at most 850 mg/day, at most 900 mg/day, atmost 950 mg/day, at most 1,000 mg/day, at most 1,50 mg/day, at most1,100 mg/day, at most 1,150 mg/day, at most 1,200 mg/day, at most 1,250mg/day, at most 1,300 mg/day, at most 1,350 mg/day, at most 1,400mg/day, at most 1,450 mg/day, at most 1,500 mg/day, at most 1,600mg/day, at most 1,700 mg/day, at most 1,800 mg/day, at most 1,900mg/day, at most 2,000 mg/day, at most 2,100 mg/day, at most 2,200mg/day, at most 2,300 mg/day, at most 2,400 mg/day, at most 2,500mg/day, at most 2,600 mg/day, at most 2,700 mg/day, at most 2,800mg/day, at most 2,900 mg/day, or at most 3,000 mg/day.

In still other aspects of this embodiment, an effective amount of atherapeutic compound disclosed herein may be between, e.g., about 40mg/day to about 250 mg/day, about 50 mg/day to about 250 mg/day, about60 mg/day to about 250 mg/day, about 70 mg/day to about 250 mg/day,about 80 mg/day to about 250 mg/day, about 90 mg/day to about 250mg/day, about 100 mg/day to about 250 mg/day, about 40 mg/day to about500 mg/day, about 50 mg/day to about 500 mg/day, about 60 mg/day toabout 500 mg/day, about 70 mg/day to about 500 mg/day, about 80 mg/dayto about 500 mg/day, about 90 mg/day to about 500 mg/day, about 100mg/day to about 500 mg/day, about 40 mg/day to about 750 mg/day, about50 mg/day to about 750 mg/day, about 60 mg/day to about 750 mg/day,about 70 mg/day to about 750 mg/day, about 80 mg/day to about 750mg/day, about 90 mg/day to about 750 mg/day, about 100 mg/day to about750 mg/day, about 50 mg/day to about 1,000 mg/day, about 100 mg/day toabout 1,000 mg/day, about 150 mg/day to about 1,000 mg/day, about 200mg/day to about 1,000 mg/day, about 250 mg/day to about 1,000 mg/day,about 300 mg/day to about 1,000 mg/day, about 350 mg/day to about 1,000mg/day, about 400 mg/day to about 1,000 mg/day, about 450 mg/day toabout 1,000 mg/day, about 500 mg/day to about 1,000 mg/day, about 50mg/day to about 1,500 mg/day, about 100 mg/day to about 1,500 mg/day,about 150 mg/day to about 1,500 mg/day, about 200 mg/day to about 1,500mg/day, about 250 mg/day to about 1,500 mg/day, about 300 mg/day toabout 1,500 mg/day, about 350 mg/day to about 1,500 mg/day, about 400mg/day to about 1,500 mg/day, about 450 mg/day to about 1,500 mg/day,about 500 mg/day to about 1,500 mg/day, about 1,000 mg/day to about3,000 mg/day, about 1,100 mg/day to about 3,000 mg/day, about 1,200mg/day to about 3,000 mg/day, about 1,3000 mg/day to about 3,000 mg/day,about 1,400 mg/day to about 3,000 mg/day, about 1,500 mg/day to about3,000 mg/day, about 1,600 mg/day to about 3,000 mg/day, about 1,700mg/day to about 3,000 mg/day, about 1,800 mg/day to about 3,000 mg/day,about 1,900 mg/day to about 3,000 mg/day, or about 2,000 mg/day to about3,000 mg/day.

In other aspects of this embodiment, a therapeutically effective amountof a methylxanthine disclosed herein generally is in the range of about0. 001 mg/kg/day to about 100 mg/kg/day. In aspects of this embodiment,an effective amount of a methylxanthine disclosed herein may be, e.g.,at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. In otheraspects of this embodiment, an effective amount of a methylxanthinedisclosed herein may be in the range of, e.g., about 0.001 mg/kg/day toabout 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet otheraspects of this embodiment, an effective amount of a methylxanthinedisclosed herein may be in the range of, e.g., about 0.01 mg/kg/day toabout 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day. In stillother aspects of this embodiment, an effective amount of amethylxanthine disclosed herein may be in the range of, e.g., about 0.1mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, an effective amount of amethylxanthine disclosed herein may be in the range of, e.g., about 1mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day toabout 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day toabout 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a methylxanthine disclosed herein maybe in the range of, e.g., about 5 mg/kg/day to about 10 mg/kg/day, about5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day to about 20mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day toabout 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day to about 45mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5 mg/kg/day toabout 75 mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, a therapeutically effective amountof a methylxanthine disclosed herein generally is in the range of about1 mg/day to about 3,000 mg/day. In aspects of this embodiment, aneffective amount of a methylxanthine disclosed herein may be, e.g., atleast 40 mg/day, at least 50 mg/day, at least 60 mg/day, at least 70mg/day, at least 80 mg/day, at least 90 mg/day, at least 100 mg/day, atleast 110 mg/day, at least 120 mg/day, at least 130 mg/day, at least 140mg/day, at least 150 mg/day, at least 160 mg/day, at least 170 mg/day,at least 180 mg/day, at least 190 mg/day, at least 200 mg/day, at least210 mg/day, at least 220 mg/day, at least 230 mg/day, at least 240mg/day, at least 250 mg/day, at least 300 mg/day, at least 350 mg/day,at least 400 mg/day, at least 450 mg/day, at least 500 mg/day, at least550 mg/day, at least 600 mg/day, at least 650 mg/day, at least 700mg/day, at least 750 mg/day, at least 800 mg/day, at least 850 mg/day,at least 900 mg/day, at least 950 mg/day, at least 1,000 mg/day, atleast 1,50 mg/day, at least 1,100 mg/day, at least 1,150 mg/day, atleast 1,200 mg/day, at least 1,250 mg/day, at least 1,300 mg/day, atleast 1,350 mg/day, at least 1,400 mg/day, at least 1,450 mg/day, atleast 1,500 mg/day, at least 1,600 mg/day, at least 1,700 mg/day, atleast 1,800 mg/day, at least 1,900 mg/day, at least 2,000 mg/day, atleast 2,100 mg/day, at least 2,200 mg/day, at least 2,300 mg/day, atleast 2,400 mg/day, at least 2,500 mg/day, at least 2,600 mg/day, atleast 2,700 mg/day, at least 2,800 mg/day, at least 2,900 mg/day, or atleast 3,000 mg/day. In yet aspects of this embodiment, an effectiveamount of a methylxanthine disclosed herein may be, e.g., at most 10mg/day, at most 20 mg/day, at most 30 mg/day, at most 40 mg/day, at most50 mg/day, at most 60 mg/day, at most 70 mg/day, at most 80 mg/day, atmost 90 mg/day, at most 100 mg/day, at most 110 mg/day, at most 120mg/day, at most 130 mg/day, at most 140 mg/day, at most 150 mg/day, atmost 160 mg/day, at most 170 mg/day, at most 180 mg/day, at most 190mg/day, at most 200 mg/day, at most 210 mg/day, at most 220 mg/day, atmost 230 mg/day, at most 240 mg/day, at most 250 mg/day, at most 300mg/day, at most 350 mg/day, at most 400 mg/day, at most 450 mg/day, atmost 500 mg/day, at most 550 mg/day, at most 600 mg/day, at most 650mg/day, at most 700 mg/day, at most 750 mg/day, at most 800 mg/day, atmost 850 mg/day, at most 900 mg/day, at most 950 mg/day, at most 1,000mg/day, at most 1,50 mg/day, at most 1,100 mg/day, at most 1,150 mg/day,at most 1,200 mg/day, at most 1,250 mg/day, at most 1,300 mg/day, atmost 1,350 mg/day, at most 1,400 mg/day, at most 1,450 mg/day, at most1,500 mg/day, at most 1,600 mg/day, at most 1,700 mg/day, at most 1,800mg/day, at most 1,900 mg/day, at most 2,000 mg/day, at most 2,100mg/day, at most 2,200 mg/day, at most 2,300 mg/day, at most 2,400mg/day, at most 2,500 mg/day, at most 2,600 mg/day, at most 2,700mg/day, at most 2,800 mg/day, at most 2,900 mg/day, or at most 3,000mg/day.

In still other aspects of this embodiment, an effective amount of amethylxanthine disclosed herein may be between, e.g., about 5 mg/day toabout 100 mg/day, about 5 mg/day to about 125 mg/day, about 5 mg/day toabout 150 mg/day, about 5 mg/day to about 175 mg/day, about 5 mg/day toabout 200 mg/day, about 5 mg/day to about 225 mg/day, about 5 mg/day toabout 250 mg/day, about 10 mg/day to about 100 mg/day, about 10 mg/dayto about 125 mg/day, about 10 mg/day to about 150 mg/day, about 10mg/day to about 175 mg/day, about 10 mg/day to about 200 mg/day, about10 mg/day to about 225 mg/day, about 10 mg/day to about 250 mg/day,about 10 mg/day to about 275 mg/day, about 10 mg/day to about 300mg/day, about 25 mg/day to about 100 mg/day, about 25 mg/day to about125 mg/day, about 25 mg/day to about 150 mg/day, about 25 mg/day toabout 175 mg/day, about 25 mg/day to about 200 mg/day, about 25 mg/dayto about 225 mg/day, about 25 mg/day to about 250 mg/day, about 25mg/day to about 275 mg/day, about 25 mg/day to about 300 mg/day, about40 mg/day to about 100 mg/day, about 40 mg/day to about 125 mg/day,about 40 mg/day to about 150 mg/day, about 40 mg/day to about 175mg/day, about 40 mg/day to about 200 mg/day, about 40 mg/day to about225 mg/day, about 40 mg/day to about 250 mg/day, about 40 mg/day toabout 275 mg/day, about 40 mg/day to about 300 mg/day, about 50 mg/dayto about 100 mg/day, about 50 mg/day to about 125 mg/day, about 50mg/day to about 150 mg/day, about 50 mg/day to about 175 mg/day, about50 mg/day to about 200 mg/day, about 50 mg/day to about 225 mg/day,about 50 mg/day to about 250 mg/day, about 50 mg/day to about 275mg/day, about 50 mg/day to about 300 mg/day, about 75 mg/day to about100 mg/day, about 75 mg/day to about 125 mg/day, about 75 mg/day toabout 150 mg/day, about 75 mg/day to about 175 mg/day, about 75 mg/dayto about 200 mg/day, about 75 mg/day to about 225 mg/day, about 75mg/day to about 250 mg/day, about 75 mg/day to about 275 mg/day, about75 mg/day to about 300 mg/day, about 75 mg/day to about 325 mg/day,about 75 mg/day to about 350 mg/day, about 75 mg/day to about 375mg/day, about 75 mg/day to about 400 mg/day, about 75 mg/day to about425 mg/day, about 75 mg/day to about 450 mg/day, about 75 mg/day toabout 475 mg/day, about 75 mg/day to about 500 mg/day, about 75 mg/dayto about 525 mg/day, about 75 mg/day to about 550 mg/day, about 75mg/day to about 575 mg/day, about 75 mg/day to about 600 mg/day, about100 mg/day to about 150 mg/day, about 100 mg/day to about 200 mg/day,about 100 mg/day to about 250 mg/day, about 100 mg/day to about 300mg/day, about 100 mg/day to about 350 mg/day, about 100 mg/day to about400 mg/day, about 100 mg/day to about 450 mg/day, about 100 mg/day toabout 500 mg/day, about 100 mg/day to about 550 mg/day, about 100 mg/dayto about 600 mg/day, about 100 mg/day to about 650 mg/day, about 100mg/day to about 700 mg/day, about 100 mg/day to about 750 mg/day, about150 mg/day to about 200 mg/day, about 150 mg/day to about 250 mg/day,about 150 mg/day to about 300 mg/day, about 150 mg/day to about 350mg/day, about 150 mg/day to about 400 mg/day, about 150 mg/day to about450 mg/day, about 150 mg/day to about 500 mg/day, about 150 mg/day toabout 550 mg/day, about 150 mg/day to about 600 mg/day, about 150 mg/dayto about 650 mg/day, about 150 mg/day to about 700 mg/day, about 150mg/day to about 750 mg/day, about 200 mg/day to about 250 mg/day, about200 mg/day to about 300 mg/day, about 200 mg/day to about 350 mg/day,about 200 mg/day to about 400 mg/day, about 200 mg/day to about 450mg/day, about 200 mg/day to about 500 mg/day, about 200 mg/day to about550 mg/day, about 200 mg/day to about 600 mg/day, about 200 mg/day toabout 650 mg/day, about 200 mg/day to about 700 mg/day, about 200 mg/dayto about 750 mg/day, about 200 mg/day to about 800 mg/day, about 250mg/day to about 300 mg/day, about 250 mg/day to about 350 mg/day, about250 mg/day to about 400 mg/day, about 250 mg/day to about 450 mg/day,about 250 mg/day to about 500 mg/day, about 250 mg/day to about 550mg/day, about 250 mg/day to about 600 mg/day, about 250 mg/day to about650 mg/day, about 250 mg/day to about 700 mg/day, about 250 mg/day toabout 750 mg/day, about 250 mg/day to about 800 mg/day, about 250 mg/dayto about 850 mg/day, about 250 mg/day to about 900 mg/day, about 250mg/day to about 950 mg/day, about 250 mg/day to about 1000 mg/day, about50 mg/day to about 1,000 mg/day, about 100 mg/day to about 1,000 mg/day,about 150 mg/day to about 1,000 mg/day, about 200 mg/day to about 1,000mg/day, about 250 mg/day to about 1,000 mg/day, about 300 mg/day toabout 1,000 mg/day, about 350 mg/day to about 1,000 mg/day, about 400mg/day to about 1,000 mg/day, about 450 mg/day to about 1,000 mg/day,about 500 mg/day to about 1,000 mg/day, about 50 mg/day to about 1,500mg/day, about 100 mg/day to about 1,500 mg/day, about 150 mg/day toabout 1,500 mg/day, about 200 mg/day to about 1,500 mg/day, about 250mg/day to about 1,500 mg/day, about 300 mg/day to about 1,500 mg/day,about 350 mg/day to about 1,500 mg/day, about 400 mg/day to about 1,500mg/day, about 450 mg/day to about 1,500 mg/day, about 500 mg/day toabout 1,500 mg/day, about 1,000 mg/day to about 3,000 mg/day, about1,100 mg/day to about 3,000 mg/day, about 1,200 mg/day to about 3,000mg/day, about 1,3000 mg/day to about 3,000 mg/day, about 1,400 mg/day toabout 3,000 mg/day, about 1,500 mg/day to about 3,000 mg/day, about1,600 mg/day to about 3,000 mg/day, about 1,700 mg/day to about 3,000mg/day, about 1,800 mg/day to about 3,000 mg/day, about 1,900 mg/day toabout 3,000 mg/day, or about 2,000 mg/day to about 3,000 mg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a non-opiate antitussive disclosedherein generally is in the range of about 0.01 mg/kg/day to about 50mg/kg/day. In other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of a non-opiate antitussivedisclosed herein may be, e.g., at least 0.01 mg/kg/day, at least 0.025mg/kg/day, at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least0.1 mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least5.0 mg/kg/day, at least 7.5 mg/kg/day, at least 10 mg/kg/day, at least25 mg/kg/day, or at least 50 mg/kg/day. In yet other aspects of thisembodiment, in conjunction with a methylxanthine, an effective amount ofa non-opiate antitussive disclosed herein may be, e.g., at least 0.1mg/kg/day, at least 0.2 mg/kg/day, at least 0.3 mg/kg/day, at least 0.4mg/kg/day, at least 0.5 mg/kg/day, at least 0.6 mg/kg/day, at least 0.7mg/kg/day, at least 0.8 mg/kg/day, at least 0.9 mg/kg/day, at least 1.0mg/kg/day, at least 1.25 mg/kg/day, at least 1.5 mg/kg/day, at least1.75 mg/kg/day, at least 2.0 mg/kg/day, at least 2.25 mg/kg/day, atleast 2.5 mg/kg/day, at least 2.75 mg/kg/day, at least 3.0 mg/kg/day, atleast 3.25 mg/kg/day, at least 3.5 mg/kg/day, at least 3.75 mg/kg/day,at least 4.0 mg/kg/day, at least 4.25 mg/kg/day, at least 4.5 mg/kg/day,at least 4.75 mg/kg/day, or at least 5.0 mg/kg/day. In yet other aspectsof this embodiment, in conjunction with a methylxanthine, an effectiveamount of a non-opiate antitussive disclosed herein may be, e.g., about0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.5mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/day, about 0.01mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to about 10mg/kg/day, about 0.1 mg/kg/day to about 0.1 mg/kg/day, about 0.1mg/kg/day to about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 1mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a non-opiate antitussive disclosedherein generally is in the range of about 1 mg/day to about 500 mg/day.In other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of a non-opiate antitussivedisclosed herein may be, e.g., at least 1 mg/day, at least 5 mg/day, atleast 10 mg/day, at least 15 mg/day, at least 20 mg/day, at least 25mg/day, at least 30 mg/day, at least 35 mg/day, at least 40 mg/day, atleast 45 mg/day, at least 50 mg/day, at least 55 mg/day at least 60mg/day at least 65 mg/day at least 70 mg/day at least 75 mg/day, atleast 100 mg/day, at least 150 mg/day, at least 200 mg/day, at least 250mg/day, at least 300 mg/day, at least 350 mg/day, at least 400 mg/day,at least 450 mg/day, or at least 500 mg/day. In yet other aspects ofthis embodiment, in conjunction with a methylxanthine, an effectiveamount of a non-opiate antitussive disclosed herein may be, e.g., atmost 1 mg/day, at most 5 mg/day, at most 10 mg/day, at most 15 mg/day,at most 20 mg/day, at most 25 mg/day, at most 30 mg/day, at most 35mg/day, at most 40 mg/day, at most 45 mg/day, at most 50 mg/day, at most55 mg/day, at most 60 mg/day, at most 65 mg/day, at most 70 mg/day, atmost 75 mg/day, at most 80 mg/day, at most 85 mg/day, at most 90 mg/day,at most 95 mg/day, at most 100 mg/day, at most 110 mg/day, at most 120mg/day, at most 130 mg/day, at most 140 mg/day, at most 150 mg/day, atmost 160 mg/day, at most 170 mg/day, at most 180 mg/day, at most 190mg/day, at most 200 mg/day, at most 250 mg/day, at most 300 mg/day, atmost 350 mg/day, at most 400 mg/day, at most 450 mg/day, or at most 500mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of a non-opiate antitussivedisclosed herein may be, e.g., about 1 mg/day to about 100 mg/day, about1 mg/day to about 150 mg/day, about 1 mg/day to about 200 mg/day, about1 mg/day to about 250 mg/day, about 1 mg/day to about 300 mg/day, about1 mg/day to about 350 mg/day, about 1 mg/day to about 400 mg/day, about1 mg/day to about 450 mg/day, about 1 mg/day to about 500 mg/day, about10 mg/day to about 100 mg/day, about 10 mg/day to about 125 mg/day,about 10 mg/day to about 150 mg/day, about 10 mg/day to about 175mg/day, about 10 mg/day to about 200 mg/day, about 10 mg/day to about250 mg/day, about 10 mg/day to about 300 mg/day, about 10 mg/day toabout 350 mg/day, about 10 mg/day to about 400 mg/day, about 10 mg/dayto about 450 mg/day, about 10 mg/day to about 500 mg/day, about 20mg/day to about 100 mg/day, about 20 mg/day to about 125 mg/day, about20 mg/day to about 150 mg/day, about 20 mg/day to about 175 mg/day,about 20 mg/day to about 200 mg/day, about 20 mg/day to about 250mg/day, about 20 mg/day to about 300 mg/day, about 20 mg/day to about350 mg/day, about 20 mg/day to about 400 mg/day, about 20 mg/day toabout 450 mg/day, about 20 mg/day to about 500 mg/day, about 30 mg/dayto about 100 mg/day, about 30 mg/day to about 120 mg/day, about 30mg/day to about 125 mg/day, about 30 mg/day to about 150 mg/day, about30 mg/day to about 175 mg/day, about 30 mg/day to about 200 mg/day,about 30 mg/day to about 250 mg/day, about 30 mg/day to about 300mg/day, about 30 mg/day to about 350 mg/day, about 30 mg/day to about400 mg/day, about 30 mg/day to about 450 mg/day, or about 30 mg/day toabout 500 mg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of an opiate antitussive disclosedherein generally is in the range of about 0.01 mg/kg/day to about 10mg/kg/day. In other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an opiate antitussive disclosedherein may be, e.g., at least 0.01 mg/kg/day, at least 0.025 mg/kg/day,at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least 0.1mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least5.0 mg/kg/day, at least 7.5 mg/kg/day, or at least 10 mg/kg/day. In yetother aspects of this embodiment, in conjunction with a methylxanthine,an effective amount of an opiate antitussive disclosed herein may be,e.g., about 0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.01 mg/kg/dayto about 0.5 mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/day, about0.01 mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to about 10mg/kg/day, about 0.1 mg/kg/day to about 0.1 mg/kg/day, about 0.1mg/kg/day to about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 1mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of an opiate antitussive disclosedherein generally is in the range of about 0.1 mg/day to about 100mg/day. In other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an opiate antitussive disclosedherein may be, e.g., at least 0.1 mg/day, at least 0.5 mg/day, at least1 mg/day, at least 2 mg/day, at least 3 mg/day, at least 4 mg/day, atleast 5 mg/day, at least 6 mg/day, at least 7 mg/day, at least 8 mg/day,at least 9 mg/day, at least 10 mg/day, at least 15 mg/day, at least 20mg/day, at least 25 mg/day, at least 30 mg/day, at least 40 mg/day, atleast 50 mg/day, at least 60 mg/day, at least 70 mg/day, at least 80mg/day, at least 90 mg/day, or at least 100 mg/day. In yet other aspectsof this embodiment, in conjunction with a methylxanthine, an effectiveamount of an opiate antitussive disclosed herein may be, e.g., at most0.1 mg/day, at most 0.5 mg/day, at most 1 mg/day, at most 2 mg/day, atmost 3 mg/day, at most 4 mg/day, at most 5 mg/day, at most 6 mg/day, atmost 7 mg/day, at most 8 mg/day, at most 9 mg/day, at most 10 mg/day, atmost 15 mg/day, at most 20 mg/day, at most 25 mg/day, at most 30 mg/day,at most 40 mg/day, at most 50 mg/day, at most 60 mg/day, at most 70mg/day, at most 80 mg/day, at most 90 mg/day, or at most 100 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an opiate antitussive disclosedherein may be, e.g., about 0.1 mg/day to about 5 mg/day, about 0.1mg/day to about 10 mg/day, about 0.1 mg/day to about 15 mg/day, about0.1 mg/day to about 20 mg/day, about 0.1 mg/day to about 25 mg/day,about 0.1 mg/day to about 30 mg/day, about 0.1 mg/day to about 40mg/day, about 0.1 mg/day to about 60 mg/day, about 0.1 mg/day to about80 mg/day, about 0.1 mg/day to about 100 mg/day, about 0.5 mg/day toabout 5 mg/day, about 0.5 mg/day to about 10 mg/day, about 0.5 mg/day toabout 15 mg/day, about 0.5 mg/day to about 20 mg/day, about 0.5 mg/dayto about 25 mg/day, about 0.5 mg/day to about 30 mg/day, about 0.5mg/day to about 40 mg/day, about 0.5 mg/day to about 60 mg/day, about0.5 mg/day to about 80 mg/day, about 0.5 mg/day to about 100 mg/day,about 1 mg/day to about 5 mg/day, about 1 mg/day to about 10 mg/day,about 1 mg/day to about 15 mg/day, about 1 mg/day to about 20 mg/day,about 1 mg/day to about 25 mg/day, about 1 mg/day to about 30 mg/day,about 1 mg/day to about 40 mg/day, about 1 mg/day to about 60 mg/day,about 1 mg/day to about 80 mg/day, about 1 mg/day to about 100 mg/day,about 2.5 mg/day to about 10 mg/day, about 2.5 mg/day to about 20mg/day, about 2.5 mg/day to about 40 mg/day, about 2.5 mg/day to about60 mg/day, about 2.5 mg/day to about 80 mg/day, or about 2.5 mg/day toabout 100 mg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a decongestant, anexpectorant, and/or a mucolytic agent disclosed herein generally is inthe range of about 0. 001 mg/kg/day to about 100 mg/kg/day. In aspectsof this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a decongestant, an expectorant,and/or a mucolytic agent disclosed herein may be, e.g., at least 0.001mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45mg/kg/day, or at least 50 mg/kg/day. In other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a decongestant, an expectorant, and/or a mucolyticagent disclosed herein may be in the range of, e.g., about 0.001mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100mg/kg/day. In yet other aspects of this embodiment, in conjunction witha methylxanthine, a therapeutically effective amount of a decongestant,an expectorant, and/or a mucolytic agent disclosed herein may be in therange of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01mg/kg/day to about 100 mg/kg/day. In still other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a decongestant, an expectorant, and/or a mucolyticagent disclosed herein may be in the range of, e.g., about 0.1 mg/kg/dayto about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a decongestant, anexpectorant, and/or a mucolytic agent disclosed herein may be in therange of, e.g., about 1 mg/kg/day to about 10 mg/kg/day, about 1mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to about 20mg/kg/day, about 1 mg/kg/day to about 25 mg/kg/day, about 1 mg/kg/day toabout 30 mg/kg/day, about 1 mg/kg/day to about 35 mg/kg/day, about 1mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day toabout 75 mg/kg/day, or about 1 mg/kg/day to about 100 mg/kg/day. In yetother aspects of this embodiment, in conjunction with a methylxanthine,a therapeutically effective amount of a decongestant, an expectorant,and/or a mucolytic agent disclosed herein may be in the range of, e.g.,about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day to about 15mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day toabout 25 mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day toabout 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/day, or about 5mg/kg/day to about 100 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a decongestant, an expectorant,and/or a mucolytic agent disclosed herein generally is in the range ofabout 0.1 mg/day to about 6,000 mg/day. In other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a decongestant, an expectorant, and/or a mucolyticagent disclosed herein may be, e.g., at least 0.1 mg/day, at least 0.5mg/day, at least 1 mg/day, at least 2 mg/day, at least 3 mg/day, atleast 4 mg/day, at least 5 mg/day, at least 6 mg/day, at least 7 mg/day,at least 8 mg/day, at least 9 mg/day, at least 10 mg/day, at least 15mg/day, at least 20 mg/day, at least 25 mg/day, at least 30 mg/day, atleast 40 mg/day, at least 50 mg/day, at least 100 mg/day, at least 150mg/day, at least 200 mg/day, at least 250 mg/day, at least 300 mg/day,at least 350 mg/day, at least 400 mg/day, at least 450 mg/day, at least500 mg/day, at least 550 mg/day, at least 600 mg/day, at least 650mg/day, at least 700 mg/day, at least 750 mg/day, at least 800 mg/day,at least 850 mg/day, at least 900 mg/day, at least 950 mg/day, at least1,000 mg/day, at least 1,50 mg/day, at least 1,100 mg/day, at least1,150 mg/day, at least 1,200 mg/day, at least 1,250 mg/day, at least1,300 mg/day, at least 1,350 mg/day, at least 1,400 mg/day, at least1,450 mg/day, at least 1,500 mg/day, at least 1,600 mg/day, at least1,700 mg/day, at least 1,800 mg/day, at least 1,900 mg/day, at least2,000 mg/day, at least 2,100 mg/day, at least 2,200 mg/day, at least2,300 mg/day, at least 2,400 mg/day, at least 2,500 mg/day, at least2,600 mg/day, at least 2,700 mg/day, at least 2,800 mg/day, at least2,900 mg/day, at least 3,000 mg/day, at least 3,500 mg/day, at least4,000 mg/day, at least 4,500 mg/day, at least 5,000 mg/day, at least5,500 mg/day, or at least 6,000 mg/day. In yet other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a decongestant, an expectorant, and/or a mucolyticagent disclosed herein may be, e.g., at most 0.1 mg/day, at most 0.5mg/day, at most 1 mg/day, at most 2 mg/day, at most 3 mg/day, at most 4mg/day, at most 5 mg/day, at most 6 mg/day, at most 7 mg/day, at most 8mg/day, at most 9 mg/day, at most 10 mg/day, at most 15 mg/day, at most20 mg/day, at most 25 mg/day, at most 30 mg/day, at most 40 mg/day, atmost 50 mg/day, at most 100 mg/day, at most 150 mg/day, at most 200mg/day, at most 250 mg/day, at most 300 mg/day, at most 350 mg/day, atmost 400 mg/day, at most 450 mg/day, at most 500 mg/day, at most 550mg/day, at most 600 mg/day, at most 650 mg/day, at most 700 mg/day, atmost 750 mg/day, at most 800 mg/day, at most 850 mg/day, at most 900mg/day, at most 950 mg/day, at most 1,000 mg/day, at most 1,50 mg/day,at most 1,100 mg/day, at most 1,150 mg/day, at most 1,200 mg/day, atmost 1,250 mg/day, at most 1,300 mg/day, at most 1,350 mg/day, at most1,400 mg/day, at most 1,450 mg/day, at most 1,500 mg/day, at most 1,600mg/day, at most 1,700 mg/day, at most 1,800 mg/day, at most 1,900mg/day, at most 2,000 mg/day, at most 2,100 mg/day, at most 2,200mg/day, at most 2,300 mg/day, at most 2,400 mg/day, at most 2,500mg/day, at most 2,600 mg/day, at most 2,700 mg/day, at most 2,800mg/day, at most 2,900 mg/day, at most 3,000 mg/day, at most 3,500mg/day, at most 4,000 mg/day, at most 4,500 mg/day, at most 5,000mg/day, at most 5,500 mg/day, or at most 6,000 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a decongestant, anexpectorant, and/or a mucolytic agent disclosed herein may be between,e.g., about 1 mg/day to about 30 mg/day, about 5 mg/day to about 30mg/day, about 10 mg/day to about 30 mg/day, about 15 mg/day to about 30mg/day, about 1 mg/day to about 50 mg/day, about 5 mg/day to about 50mg/day, about 15 mg/day to about 50 mg/day, about 20 mg/day to about 50mg/day, about 25 mg/day to about 50 mg/day, about 1 mg/day to about 60mg/day, about 5 mg/day to about 60 mg/day, about 15 mg/day to about 60mg/day, about 25 mg/day to about 60 mg/day, about 30 mg/day to about 60mg/day, about 40 mg/day to about 60 mg/day, about 50 mg/day to about 60mg/day, about 1 mg/day to about 75 mg/day, about 5 mg/day to about 75mg/day, about 15 mg/day to about 75 mg/day, about 20 mg/day to about 75mg/day, about 25 mg/day to about 75 mg/day, about 30 mg/day to about 75mg/day, about 40 mg/day to about 75 mg/day, about 50 mg/day to about 75mg/day, about 1 mg/day to about 100 mg/day, about 25 mg/day to about 100mg/day, about 50 mg/day to about 100 mg/day, about 75 mg/day to about100 mg/day, about 1 mg/day to about 250 mg/day, about 25 mg/day to about250 mg/day, about 50 mg/day to about 250 mg/day, about 100 mg/day toabout 250 mg/day, about 150 mg/day to about 250 mg/day, about 200 mg/dayto about 250 mg/day, about 1 mg/day to about 500 mg/day, about 25 mg/dayto about 500 mg/day, about 50 mg/day to about 500 mg/day, about 100mg/day to about 500 mg/day, about 150 mg/day to about 500 mg/day, about200 mg/day to about 500 mg/day, about 250 mg/day to about 500 mg/day,about 300 mg/day to about 500 mg/day, about 350 mg/day to about 500mg/day, about 400 mg/day to about 500 mg/day, about 450 mg/day to about500 mg/day, about 1 mg/day to about 1,000 mg/day, about 25 mg/day toabout 1,000 mg/day, about 50 mg/day to about 1,000 mg/day, about 100mg/day to about 1,000 mg/day, about 150 mg/day to about 1,000 mg/day,about 200 mg/day to about 1,000 mg/day, about 250 mg/day to about 1,000mg/day, about 300 mg/day to about 1,000 mg/day, about 350 mg/day toabout 1,000 mg/day, about 400 mg/day to about 1,000 mg/day, about 450mg/day to about 1,000 mg/day, about 500 mg/day to about 1,000 mg/day,about 50 mg/day to about 1,500 mg/day, about 100 mg/day to about 1,500mg/day, about 150 mg/day to about 1,500 mg/day, about 200 mg/day toabout 1,500 mg/day, about 250 mg/day to about 1,500 mg/day, about 300mg/day to about 1,500 mg/day, about 350 mg/day to about 1,500 mg/day,about 400 mg/day to about 1,500 mg/day, about 450 mg/day to about 1,500mg/day, about 500 mg/day to about 1,500 mg/day, about 1,000 mg/day toabout 3,000 mg/day, about 1,100 mg/day to about 3,000 mg/day, about1,200 mg/day to about 3,000 mg/day, about 1,3000 mg/day to about 3,000mg/day, about 1,400 mg/day to about 3,000 mg/day, about 1,500 mg/day toabout 3,000 mg/day, about 1,600 mg/day to about 3,000 mg/day, about1,700 mg/day to about 3,000 mg/day, about 1,800 mg/day to about 3,000mg/day, about 1,900 mg/day to about 3,000 mg/day, about 2,000 mg/day toabout 3,000 mg/day, about 1,000 mg/day to about 4,000 mg/day, about1,100 mg/day to about 4,000 mg/day, about 1,200 mg/day to about 4,000mg/day, about 1,3000 mg/day to about 4,000 mg/day, about 1,400 mg/day toabout 4,000 mg/day, about 1,500 mg/day to about 4,000 mg/day, about1,600 mg/day to about 4,000 mg/day, about 1,700 mg/day to about 4,000mg/day, about 1,800 mg/day to about 4,000 mg/day, about 1,900 mg/day toabout 4,000 mg/day, about 2,000 mg/day to about 4,000 mg/day, about2,500 mg/day to about 4,000 mg/day, about 3,000 mg/day to about 4,000mg/day, about 1,000 mg/day to about 5,000 mg/day, about 1,100 mg/day toabout 5,000 mg/day, about 1,200 mg/day to about 5,000 mg/day, about1,3000 mg/day to about 5,000 mg/day, about 1,400 mg/day to about 5,000mg/day, about 1,500 mg/day to about 5,000 mg/day, about 1,600 mg/day toabout 5,000 mg/day, about 1,700 mg/day to about 5,000 mg/day, about1,800 mg/day to about 5,000 mg/day, about 1,900 mg/day to about 5,000mg/day, about 2,000 mg/day to about 5,000 mg/day, about 2,500 mg/day toabout 5,000 mg/day, about 3,000 mg/day to about 5,000 mg/day, about3,500 mg/day to about 5,000 mg/day, about 4,000 mg/day to about 5,000mg/day, about 1,000 mg/day to about 6,000 mg/day, about 1,100 mg/day toabout 6,000 mg/day, about 1,200 mg/day to about 6,000 mg/day, about1,3000 mg/day to about 6,000 mg/day, about 1,400 mg/day to about 6,000mg/day, about 1,500 mg/day to about 6,000 mg/day, about 1,600 mg/day toabout 6,000 mg/day, about 1,700 mg/day to about 6,000 mg/day, about1,800 mg/day to about 6,000 mg/day, about 1,900 mg/day to about 6,000mg/day, about 2,000 mg/day to about 6,000 mg/day, about 2,500 mg/day toabout 6,000 mg/day, about 3,000 mg/day to about 6,000 mg/day, about3,500 mg/day to about 6,000 mg/day, about 4,000 mg/day to about 6,000mg/day, about 4,500 mg/day to about 6,000 mg/day, or about 5,000 mg/dayto about 6,000 mg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of an antihistamine disclosed hereingenerally is in the range of about 0.001 mg/kg/day to about 50mg/kg/day. In other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an antihistamine disclosed hereinmay be, e.g., at least 0.001 mg/kg/day, at least 0.0025 mg/kg/day, atleast 0.005 mg/kg/day, at least 0.0075 mg/kg/day, at least 0.01mg/kg/day, at least 0.025 mg/kg/day, at least 0.05 mg/kg/day, at least0.075 mg/kg/day, at least 0.1 mg/kg/day, at least 0.25 mg/kg/day, atleast 0.5 mg/kg/day, at least 0.75 mg/kg/day, at least 1.0 mg/kg/day, atleast 2.5 mg/kg/day, at least 5.0 mg/kg/day, at least 7.5 mg/kg/day, atleast 10 mg/kg/day, at least 25 mg/kg/day, or at least 50 mg/kg/day. Inyet other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an antihistamine disclosed hereinmay be, e.g., at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, at least0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, at least0.6 mg/kg/day, at least 0.7 mg/kg/day, at least 0.8 mg/kg/day, at least0.9 mg/kg/day, at least 1.0 mg/kg/day, at least 1.25 mg/kg/day, at least1.5 mg/kg/day, at least 1.75 mg/kg/day, at least 2.0 mg/kg/day, at least2.25 mg/kg/day, at least 2.5 mg/kg/day, at least 2.75 mg/kg/day, atleast 3.0 mg/kg/day, at least 3.25 mg/kg/day, at least 3.5 mg/kg/day, atleast 3.75 mg/kg/day, at least 4.0 mg/kg/day, at least 4.25 mg/kg/day,at least 4.5 mg/kg/day, at least 4.75 mg/kg/day, or at least 5.0mg/kg/day. In yet other aspects of this embodiment, in conjunction witha methylxanthine, an effective amount of an antihistamine disclosedherein may be, e.g., about 0.001 mg/kg/day to about 0.1 mg/kg/day, about0.001 mg/kg/day to about 0.5 mg/kg/day, about 0.001 mg/kg/day to about 1mg/kg/day, about 0.001 mg/kg/day to about 5 mg/kg/day, about 0.001mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 0.1mg/kg/day, about 0.01 mg/kg/day to about 0.5 mg/kg/day, about 0.01mg/kg/day to about 1 mg/kg/day, about 0.01 mg/kg/day to about 5mg/kg/day, about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.1mg/kg/day to about 0.1 mg/kg/day, about 0.1 mg/kg/day to about 0.5mg/kg/day, about 0.1 mg/kg/day to about 1 mg/kg/day, about 0.1 mg/kg/dayto about 5 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of an antihistamine disclosed hereingenerally is in the range of about 1 mg/day to about 500 mg/day. Inother aspects of this embodiment, in conjunction with a methylxanthine,an effective amount of an antihistamine disclosed herein may be, e.g.,at least 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least 15mg/day, at least 20 mg/day, at least 25 mg/day, at least 30 mg/day, atleast 35 mg/day, at least 40 mg/day, at least 45 mg/day, at least 50mg/day, at least 55 mg/day at least 60 mg/day at least 65 mg/day atleast 70 mg/day at least 75 mg/day, at least 100 mg/day, at least 150mg/day, at least 200 mg/day, at least 250 mg/day, at least 300 mg/day,at least 350 mg/day, at least 400 mg/day, at least 450 mg/day, or atleast 500 mg/day. In yet other aspects of this embodiment, inconjunction with a methylxanthine, an effective amount of anantihistamine disclosed herein may be, e.g., at most 1 mg/day, at most 5mg/day, at most 10 mg/day, at most 15 mg/day, at most 20 mg/day, at most25 mg/day, at most 30 mg/day, at most 35 mg/day, at most 40 mg/day, atmost 45 mg/day, at most 50 mg/day, at most 55 mg/day, at most 60 mg/day,at most 65 mg/day, at most 70 mg/day, at most 75 mg/day, at most 80mg/day, at most 85 mg/day, at most 90 mg/day, at most 95 mg/day, at most100 mg/day, at most 110 mg/day, at most 120 mg/day, at most 130 mg/day,at most 140 mg/day, at most 150 mg/day, at most 160 mg/day, at most 170mg/day, at most 180 mg/day, at most 190 mg/day, at most 200 mg/day, atmost 250 mg/day, at most 300 mg/day, at most 350 mg/day, at most 400mg/day, at most 450 mg/day, or at most 500 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an antihistamine disclosed hereinmay be, e.g., about 1 mg/day to about 100 mg/day, about 1 mg/day toabout 150 mg/day, about 1 mg/day to about 200 mg/day, about 1 mg/day toabout 250 mg/day, about 1 mg/day to about 300 mg/day, about 1 mg/day toabout 350 mg/day, about 1 mg/day to about 400 mg/day, about 1 mg/day toabout 450 mg/day, about 1 mg/day to about 500 mg/day, about 10 mg/day toabout 100 mg/day, about 10 mg/day to about 125 mg/day, about 10 mg/dayto about 150 mg/day, about 10 mg/day to about 175 mg/day, about 10mg/day to about 200 mg/day, about 10 mg/day to about 250 mg/day, about10 mg/day to about 300 mg/day, about 10 mg/day to about 350 mg/day,about 10 mg/day to about 400 mg/day, about 10 mg/day to about 450mg/day, about 10 mg/day to about 500 mg/day, about 20 mg/day to about100 mg/day, about 20 mg/day to about 125 mg/day, about 20 mg/day toabout 150 mg/day, about 20 mg/day to about 175 mg/day, about 20 mg/dayto about 200 mg/day, about 20 mg/day to about 250 mg/day, about 20mg/day to about 300 mg/day, about 20 mg/day to about 350 mg/day, about20 mg/day to about 400 mg/day, about 20 mg/day to about 450 mg/day,about 20 mg/day to about 500 mg/day, about 30 mg/day to about 100mg/day, about 30 mg/day to about 120 mg/day, about 30 mg/day to about125 mg/day, about 30 mg/day to about 150 mg/day, about 30 mg/day toabout 175 mg/day, about 30 mg/day to about 200 mg/day, about 30 mg/dayto about 250 mg/day, about 30 mg/day to about 300 mg/day, about 30mg/day to about 350 mg/day, about 30 mg/day to about 400 mg/day, about30 mg/day to about 450 mg/day, about 30 mg/day to about 500 mg/day,about 37.5 mg/day to about 100 mg/day, about 37.5 mg/day to about 120mg/day, about 37.5 mg/day to about 125 mg/day, about 37.5 mg/day toabout 150 mg/day, about 37.5 mg/day to about 175 mg/day, about 37.5mg/day to about 200 mg/day, about 37.5 mg/day to about 250 mg/day, about37.5 mg/day to about 300 mg/day, about 37.5 mg/day to about 350 mg/day,about 37.5 mg/day to about 400 mg/day, about 37.5 mg/day to about 450mg/day, or about 37.5 mg/day to about 500 mg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a NSAID disclosedherein generally is in the range of about 0. 001 mg/kg/day to about 100mg/kg/day. In aspects of this embodiment, an effective amount of amethylxanthine disclosed herein may be, e.g., at least 0.001 mg/kg/day,at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day,at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, atleast 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, atleast 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or atleast 50 mg/kg/day. In other aspects of this embodiment, in conjunctionwith a methylxanthine, a therapeutically effective amount of a NSAIDdisclosed herein may be in the range of, e.g., about 0.001 mg/kg/day toabout 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet otheraspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a NSAID disclosed herein may be inthe range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01mg/kg/day to about 100 mg/kg/day. In still other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a NSAID disclosed herein may be in the range of,e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day toabout 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100mg/kg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a NSAID disclosedherein may be in the range of, e.g., about 1 mg/kg/day to about 10mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day toabout 20 mg/kg/day, about 1 mg/kg/day to about 25 mg/kg/day, about 1mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day to about 35mg/kg/day, about 1 mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day toabout 45 mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/day, about 1mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to about 100mg/kg/day. In yet other aspects of this embodiment, in conjunction witha methylxanthine, a therapeutically effective amount of a NSAIDdisclosed herein may be in the range of, e.g., about 5 mg/kg/day toabout 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day to about 25mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day toabout 35 mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day to about 50mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/dayto about 100 mg/kg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a NSAID disclosedherein generally is in the range of about 1 mg/day to about 1,200mg/day. In aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a NSAID disclosedherein may be, e.g., at least 50 mg/day, at least 100 mg/day, at least150 mg/day, at least 200 mg/day, at least 250 mg/day, at least 300mg/day, at least 350 mg/day, at least 400 mg/day, at least 450 mg/day,at least 500 mg/day, at least 550 mg/day, at least 600 mg/day, at least650 mg/day, at least 700 mg/day, at least 750 mg/day, at least 800mg/day, at least 850 mg/day, at least 900 mg/day, at least 950 mg/day,at least 1,000 mg/day, at least 1,050 mg/day, at least 1,100 mg/day, atleast 1,150 mg/day, or at least 1,200 mg/day. In aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a NSAID disclosed herein may be, e.g., at most 50mg/day, at most 100 mg/day, at most 150 mg/day, at most 200 mg/day, atmost 250 mg/day, at most 300 mg/day, at most 350 mg/day, at most 400mg/day, at most 450 mg/day, at most 500 mg/day, at most 550 mg/day, atmost 600 mg/day, at most 650 mg/day, at most 700 mg/day, at most 750mg/day, at most 800 mg/day, at most 850 mg/day, at most 900 mg/day, atmost 950 mg/day, at most 1,000 mg/day, at most 1,050 mg/day, at most1,100 mg/day, at most 1,150 mg/day, or at most 1,200 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a NSAID disclosedherein may be between, e.g., about 50 mg/day to about 800 mg/day, about100 mg/day to about 800 mg/day, about 150 mg/day to about 800 mg/day,about 200 mg/day to about 800 mg/day, about 250 mg/day to about 800mg/day, about 300 mg/day to about 800 mg/day, about 350 mg/day to about800 mg/day, about 400 mg/day to about 800 mg/day, about 450 mg/day toabout 800 mg/day, about 500 mg/day to about 800 mg/day, about 50 mg/dayto about 1,000 mg/day, about 100 mg/day to about 1,000 mg/day, about 150mg/day to about 1,000 mg/day, about 200 mg/day to about 1,000 mg/day,about 250 mg/day to about 1,000 mg/day, about 300 mg/day to about 1,000mg/day, about 350 mg/day to about 1,000 mg/day, about 400 mg/day toabout 1,000 mg/day, about 450 mg/day to about 1,000 mg/day, about 500mg/day to about 1,000 mg/day, about 50 mg/day to about 1,200 mg/day,about 100 mg/day to about 1,200 mg/day, about 150 mg/day to about 1,200mg/day, about 200 mg/day to about 1,200 mg/day, about 250 mg/day toabout 1,200 mg/day, about 300 mg/day to about 1,200 mg/day, about 350mg/day to about 1,200 mg/day, about 400 mg/day to about 1,200 mg/day,about 450 mg/day to about 1,200 mg/day, about 500 mg/day to about 1,200mg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a neuropathic painagent disclosed herein generally is in the range of about 0. 001mg/kg/day to about 100 mg/kg/day. In aspects of this embodiment, inconjunction with a methylxanthine, a therapeutically effective amount ofa neuropathic pain agent disclosed herein may be, e.g., at least 0.001mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45mg/kg/day, or at least 50 mg/kg/day. In other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a neuropathic pain agent disclosed herein may be inthe range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001mg/kg/day to about 100 mg/kg/day. In yet other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a neuropathic pain agent disclosed herein may be inthe range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01mg/kg/day to about 100 mg/kg/day. In still other aspects of thisembodiment, in conjunction with a methylxanthine, a therapeuticallyeffective amount of a neuropathic pain agent disclosed herein may be inthe range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a neuropathic painagent disclosed herein may be in the range of, e.g., about 1 mg/kg/dayto about 10 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day toabout 35 mg/kg/day, about 1 mg/kg/day to about 40 mg/kg/day, about 1mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day to about 50mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/dayto about 100 mg/kg/day. In yet other aspects of this embodiment, inconjunction with a methylxanthine, a therapeutically effective amount ofa neuropathic pain agent disclosed herein may be in the range of, e.g.,about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day to about 15mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day toabout 25 mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day toabout 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/day, or about 5mg/kg/day to about 100 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a neuropathic pain agent disclosedherein generally is in the range of about 0.1 mg/day to about 6,000mg/day. In other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a neuropathic painagent disclosed herein may be, e.g., at least 0.1 mg/day, at least 0.5mg/day, at least 1 mg/day, at least 2 mg/day, at least 3 mg/day, atleast 4 mg/day, at least 5 mg/day, at least 6 mg/day, at least 7 mg/day,at least 8 mg/day, at least 9 mg/day, at least 10 mg/day, at least 15mg/day, at least 20 mg/day, at least 25 mg/day, at least 30 mg/day, atleast 40 mg/day, at least 50 mg/day, at least 100 mg/day, at least 150mg/day, at least 200 mg/day, at least 250 mg/day, at least 300 mg/day,at least 350 mg/day, at least 400 mg/day, at least 450 mg/day, at least500 mg/day, at least 550 mg/day, at least 600 mg/day, at least 650mg/day, at least 700 mg/day, at least 750 mg/day, at least 800 mg/day,at least 850 mg/day, at least 900 mg/day, at least 950 mg/day, at least1,000 mg/day, at least 1,50 mg/day, at least 1,100 mg/day, at least1,150 mg/day, at least 1,200 mg/day, at least 1,250 mg/day, at least1,300 mg/day, at least 1,350 mg/day, at least 1,400 mg/day, at least1,450 mg/day, at least 1,500 mg/day, at least 1,600 mg/day, at least1,700 mg/day, at least 1,800 mg/day, at least 1,900 mg/day, at least2,000 mg/day, at least 2,100 mg/day, at least 2,200 mg/day, at least2,300 mg/day, at least 2,400 mg/day, at least 2,500 mg/day, at least2,600 mg/day, at least 2,700 mg/day, at least 2,800 mg/day, at least2,900 mg/day, at least 3,000 mg/day, at least 3,500 mg/day, at least4,000 mg/day, at least 4,500 mg/day, at least 5,000 mg/day, at least5,500 mg/day, at least 6,000 mg/day, at least 6,500 mg/day, at least7,000 mg/day, at least 7,500 mg/day, or at least 8,000 mg/day. In yetother aspects of this embodiment, in conjunction with a methylxanthine,a therapeutically effective amount of a neuropathic pain agent disclosedherein may be, e.g., at most 50 mg/day, at most 100 mg/day, at most 150mg/day, at most 200 mg/day, at most 250 mg/day, at most 300 mg/day, atmost 350 mg/day, at most 400 mg/day, at most 450 mg/day, at most 500mg/day, at most 550 mg/day, at most 600 mg/day, at most 650 mg/day, atmost 700 mg/day, at most 750 mg/day, at most 800 mg/day, at most 850mg/day, at most 900 mg/day, at most 950 mg/day, at most 1,000 mg/day, atmost 1,50 mg/day, at most 1,100 mg/day, at most 1,150 mg/day, at most1,200 mg/day, at most 1,250 mg/day, at most 1,300 mg/day, at most 1,350mg/day, at most 1,400 mg/day, at most 1,450 mg/day, at most 1,500mg/day, at most 1,600 mg/day, at most 1,700 mg/day, at most 1,800mg/day, at most 1,900 mg/day, at most 2,000 mg/day, at most 2,100mg/day, at most 2,200 mg/day, at most 2,300 mg/day, at most 2,400mg/day, at most 2,500 mg/day, at most 2,600 mg/day, at most 2,700mg/day, at most 2,800 mg/day, at most 2,900 mg/day, at most 3,000mg/day, at most 3,500 mg/day, at most 4,000 mg/day, at most 4,500mg/day, at most 5,000 mg/day, at most 5,500 mg/day, at most 6,000mg/day, at most 6,500 mg/day, at most 7,000 mg/day, at most 7,500mg/day, or at most 8,000 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, a therapeutically effective amount of a neuropathic painagent disclosed herein may be between, e.g., about 1 mg/day to about 30mg/day, about 5 mg/day to about 30 mg/day, about 10 mg/day to about 30mg/day, about 15 mg/day to about 30 mg/day, about 1 mg/day to about 50mg/day, about 5 mg/day to about 50 mg/day, about 15 mg/day to about 50mg/day, about 20 mg/day to about 50 mg/day, about 25 mg/day to about 50mg/day, about 1 mg/day to about 60 mg/day, about 5 mg/day to about 60mg/day, about 15 mg/day to about 60 mg/day, about 25 mg/day to about 60mg/day, about 30 mg/day to about 60 mg/day, about 40 mg/day to about 60mg/day, about 50 mg/day to about 60 mg/day, about 1 mg/day to about 75mg/day, about 5 mg/day to about 75 mg/day, about 15 mg/day to about 75mg/day, about 20 mg/day to about 75 mg/day, about 25 mg/day to about 75mg/day, about 30 mg/day to about 75 mg/day, about 40 mg/day to about 75mg/day, about 50 mg/day to about 75 mg/day, about 1 mg/day to about 100mg/day, about 25 mg/day to about 100 mg/day, about 50 mg/day to about100 mg/day, about 75 mg/day to about 100 mg/day, about 1 mg/day to about250 mg/day, about 25 mg/day to about 250 mg/day, about 50 mg/day toabout 250 mg/day, about 100 mg/day to about 250 mg/day, about 150 mg/dayto about 250 mg/day, about 200 mg/day to about 250 mg/day, about 1mg/day to about 500 mg/day, about 25 mg/day to about 500 mg/day, about50 mg/day to about 500 mg/day, about 100 mg/day to about 500 mg/day,about 150 mg/day to about 500 mg/day, about 200 mg/day to about 500mg/day, about 250 mg/day to about 500 mg/day, about 300 mg/day to about500 mg/day, about 350 mg/day to about 500 mg/day, about 400 mg/day toabout 500 mg/day, about 450 mg/day to about 500 mg/day, about 1 mg/dayto about 1,000 mg/day, about 25 mg/day to about 1,000 mg/day, about 50mg/day to about 1,000 mg/day, about 100 mg/day to about 1,000 mg/day,about 150 mg/day to about 1,000 mg/day, about 200 mg/day to about 1,000mg/day, about 250 mg/day to about 1,000 mg/day, about 300 mg/day toabout 1,000 mg/day, about 350 mg/day to about 1,000 mg/day, about 400mg/day to about 1,000 mg/day, about 450 mg/day to about 1,000 mg/day,about 500 mg/day to about 1,000 mg/day, about 50 mg/day to about 1,500mg/day, about 100 mg/day to about 1,500 mg/day, about 150 mg/day toabout 1,500 mg/day, about 200 mg/day to about 1,500 mg/day, about 250mg/day to about 1,500 mg/day, about 300 mg/day to about 1,500 mg/day,about 350 mg/day to about 1,500 mg/day, about 400 mg/day to about 1,500mg/day, about 450 mg/day to about 1,500 mg/day, about 500 mg/day toabout 1,500 mg/day, about 1,000 mg/day to about 3,000 mg/day, about1,100 mg/day to about 3,000 mg/day, about 1,200 mg/day to about 3,000mg/day, about 1,3000 mg/day to about 3,000 mg/day, about 1,400 mg/day toabout 3,000 mg/day, about 1,500 mg/day to about 3,000 mg/day, about1,600 mg/day to about 3,000 mg/day, about 1,700 mg/day to about 3,000mg/day, about 1,800 mg/day to about 3,000 mg/day, about 1,900 mg/day toabout 3,000 mg/day, about 2,000 mg/day to about 3,000 mg/day, about1,000 mg/day to about 4,000 mg/day, about 1,100 mg/day to about 4,000mg/day, about 1,200 mg/day to about 4,000 mg/day, about 1,3000 mg/day toabout 4,000 mg/day, about 1,400 mg/day to about 4,000 mg/day, about1,500 mg/day to about 4,000 mg/day, about 1,600 mg/day to about 4,000mg/day, about 1,700 mg/day to about 4,000 mg/day, about 1,800 mg/day toabout 4,000 mg/day, about 1,900 mg/day to about 4,000 mg/day, about2,000 mg/day to about 4,000 mg/day, about 2,500 mg/day to about 4,000mg/day, about 3,000 mg/day to about 4,000 mg/day, about 1,000 mg/day toabout 5,000 mg/day, about 1,100 mg/day to about 5,000 mg/day, about1,200 mg/day to about 5,000 mg/day, about 1,3000 mg/day to about 5,000mg/day, about 1,400 mg/day to about 5,000 mg/day, about 1,500 mg/day toabout 5,000 mg/day, about 1,600 mg/day to about 5,000 mg/day, about1,700 mg/day to about 5,000 mg/day, about 1,800 mg/day to about 5,000mg/day, about 1,900 mg/day to about 5,000 mg/day, about 2,000 mg/day toabout 5,000 mg/day, about 2,500 mg/day to about 5,000 mg/day, about3,000 mg/day to about 5,000 mg/day, about 3,500 mg/day to about 5,000mg/day, about 4,000 mg/day to about 5,000 mg/day, about 1,000 mg/day toabout 6,000 mg/day, about 1,100 mg/day to about 6,000 mg/day, about1,200 mg/day to about 6,000 mg/day, about 1,3000 mg/day to about 6,000mg/day, about 1,400 mg/day to about 6,000 mg/day, about 1,500 mg/day toabout 6,000 mg/day, about 1,600 mg/day to about 6,000 mg/day, about1,700 mg/day to about 6,000 mg/day, about 1,800 mg/day to about 6,000mg/day, about 1,900 mg/day to about 6,000 mg/day, about 2,000 mg/day toabout 6,000 mg/day, about 2,500 mg/day to about 6,000 mg/day, about3,000 mg/day to about 6,000 mg/day, about 3,500 mg/day to about 6,000mg/day, about 4,000 mg/day to about 6,000 mg/day, about 4,500 mg/day toabout 6,000 mg/day, or about 5,000 mg/day to about 6,000 mg/day, about2,000 mg/day to about 7,000 mg/day, about 2,500 mg/day to about 7,000mg/day, about 3,000 mg/day to about 7,000 mg/day, about 3,500 mg/day toabout 7,000 mg/day, about 4,000 mg/day to about 7,000 mg/day, about4,500 mg/day to about 7,000 mg/day, about 5,000 mg/day to about 7,000mg/day, about 5,500 mg/day to about 7,000 mg/day, or about 6,000 mg/dayto about 7,000 mg/day, about 2,000 mg/day to about 8,000 mg/day, about2,500 mg/day to about 8,000 mg/day, about 3,000 mg/day to about 8,000mg/day, about 3,500 mg/day to about 8,000 mg/day, about 4,000 mg/day toabout 8,000 mg/day, about 4,500 mg/day to about 8,000 mg/day, about5,000 mg/day to about 8,000 mg/day, about 5,500 mg/day to about 8,000mg/day, about 6,000 mg/day to about 8,000 mg/day, about 6,500 mg/day toabout 8,000 mg/day, or about 7,000 mg/day to about 8,000 mg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a terpene disclosed herein generallyis in the range of about 0.001 mg/kg/day to about 10 mg/kg/day. In otheraspects of this embodiment, in conjunction with a methylxanthine, aneffective amount of a terpene disclosed herein may be, e.g., at least0.001 mg/kg/day, at least 0.0025 mg/kg/day, at least 0.005 mg/kg/day, atleast 0.0075 mg/kg/day, at least 0.01 mg/kg/day, at least 0.025mg/kg/day, at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least0.1 mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least5.0 mg/kg/day, at least 7.5 mg/kg/day, or at least 10 mg/kg/day. In yetother aspects of this embodiment, in conjunction with a methylxanthine,an effective amount of a terpene disclosed herein may be, e.g., about0.001 mg/kg/day to about 0.1 mg/kg/day, about 0.001 mg/kg/day to about0.5 mg/kg/day, about 0.001 mg/kg/day to about 1 mg/kg/day, about 0.001mg/kg/day to about 5 mg/kg/day, about 0.001 mg/kg/day to about 10mg/kg/day, about 0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.01mg/kg/day to about 0.5 mg/kg/day, about 0.01 mg/kg/day to about 1mg/kg/day, about 0.01 mg/kg/day to about 5 mg/kg/day, about 0.01mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 0.1mg/kg/day, about 0.1 mg/kg/day to about 0.5 mg/kg/day, about 0.1mg/kg/day to about 1 mg/kg/day, about 0.1 mg/kg/day to about 5mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of a terpene disclosed herein generallyis in the range of about 0.1 mg/day to about 500 mg/day. In otheraspects of this embodiment, in conjunction with a methylxanthine, aneffective amount of a terpene disclosed herein may be, e.g., at least0.1 mg/day, at least 0.5 mg/day, at least 1 mg/day, at least 5 mg/day,at least 10 mg/day, at least 20 mg/day, at least 30 mg/day, at least 40mg/day, at least 50 mg/day, at least 60 mg/day, at least 70 mg/day, atleast 80 mg/day, at least 90 mg/day, at least 100 mg/day, at least 150mg/day, at least 200 mg/day, at least 250 mg/day, at least 300 mg/day,at least 350 mg/day, at least 400 mg/day, at least 450 mg/day, or atleast 500 mg/day. In yet other aspects of this embodiment, inconjunction with a methylxanthine, an effective amount of a terpenedisclosed herein may be, e.g., at most 0.1 mg/day, at most 0.5 mg/day,at most 1 mg/day, at most 5 mg/day, at most 10 mg/day, at most 20mg/day, at most 30 mg/day, at most 40 mg/day, at most 50 mg/day, at most60 mg/day, at most 70 mg/day, at most 80 mg/day, at most 90 mg/day, atmost 100 mg/day, at most 150 mg/day, at most 200 mg/day, at most 250mg/day, at most 300 mg/day, at most 350 mg/day, at most 400 mg/day, atmost 450 mg/day, or at most 500 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of a terpene disclosed herein maybe, e.g., about 0.1 mg/day to about 10 mg/day, about 0.1 mg/day to about20 mg/day, about 0.1 mg/day to about 40 mg/day, about 0.1 mg/day toabout 60 mg/day, about 0.1 mg/day to about 80 mg/day, about 0.1 mg/dayto about 100 mg/day, about 1 mg/day to about 10 mg/day, about 1 mg/dayto about 20 mg/day, about 1 mg/day to about 40 mg/day, about 1 mg/day toabout 60 mg/day, about 1 mg/day to about 80 mg/day, about 1 mg/day toabout 100 mg/day, about 1 mg/day to about 150 mg/day, about 1 mg/day toabout 200 mg/day, about 1 mg/day to about 250 mg/day, about 1 mg/day toabout 300 mg/day, about 1 mg/day to about 350 mg/day, about 1 mg/day toabout 400 mg/day, about 1 mg/day to about 450 mg/day, about 1 mg/day toabout 500 mg/day, about 2.5 mg/day to about 10 mg/day, about 2.5 mg/dayto about 20 mg/day, about 2.5 mg/day to about 40 mg/day, about 2.5mg/day to about 60 mg/day, about 2.5 mg/day to about 80 mg/day, about2.5 mg/day to about 100 mg/day, about 2.5 mg/day to about 100 mg/day,about 2.5 mg/day to about 150 mg/day, about 2.5 mg/day to about 200mg/day, about 2.5 mg/day to about 250 mg/day, about 2.5 mg/day to about300 mg/day, about 2.5 mg/day to about 350 mg/day, about 2.5 mg/day toabout 400 mg/day, about 2.5 mg/day to about 450 mg/day, about 2.5 mg/dayto about 500 mg/day, about 10 mg/day to about 100 mg/day, about 10mg/day to about 150 mg/day, about 10 mg/day to about 200 mg/day, about10 mg/day to about 250 mg/day, about 10 mg/day to about 300 mg/day,about 10 mg/day to about 350 mg/day, about 10 mg/day to about 400mg/day, about 10 mg/day to about 450 mg/day, or about 10 mg/day to about500 mg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of an ACE inhibitor and/or anangiotensin II receptor antagonist disclosed herein generally is in therange of about 0.01 mg/kg/day to about 10 mg/kg/day. In other aspects ofthis embodiment, in conjunction with a methylxanthine, an effectiveamount of an ACE inhibitor and/or an angiotensin II receptor antagonistdisclosed herein may be, e.g., at least 0.01 mg/kg/day, at least 0.025mg/kg/day, at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least0.1 mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least5.0 mg/kg/day, at least 7.5 mg/kg/day, or at least 10 mg/kg/day. In yetother aspects of this embodiment, in conjunction with a methylxanthine,an effective amount of an ACE inhibitor and/or an angiotensin IIreceptor antagonist disclosed herein may be, e.g., about 0.01 mg/kg/dayto about 0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.5 mg/kg/day,about 0.01 mg/kg/day to about 1 mg/kg/day, about 0.01 mg/kg/day to about5 mg/kg/day, about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.1mg/kg/day to about 0.1 mg/kg/day, about 0.1 mg/kg/day to about 0.5mg/kg/day, about 0.1 mg/kg/day to about 1 mg/kg/day, about 0.1 mg/kg/dayto about 5 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with a methylxanthine, atherapeutically effective amount of an ACE inhibitor and/or anangiotensin II receptor antagonist disclosed herein generally is in therange of about 1 mg/day to about 500 mg/day. In other aspects of thisembodiment, in conjunction with a methylxanthine, an effective amount ofan ACE inhibitor and/or an angiotensin II receptor antagonist disclosedherein may be, e.g., at least 1 mg/day, at least 5 mg/day, at least 10mg/day, at least 25 mg/day, at least 50 mg/day, at least 75 mg/day, atleast 100 mg/day, at least 150 mg/day, at least 200 mg/day, at least 250mg/day, at least 300 mg/day, at least 350 mg/day, at least 400 mg/day,at least 450 mg/day, or at least 500 mg/day. In yet other aspects ofthis embodiment, in conjunction with a methylxanthine, an effectiveamount of an ACE inhibitor and/or an angiotensin II receptor antagonistdisclosed herein may be, e.g., at most 1 mg/day, at most 5 mg/day, atmost 10 mg/day, at most 25 mg/day, at most 50 mg/day, at most 75 mg/day,at most 100 mg/day, at most 150 mg/day, at most 200 mg/day, at most 250mg/day, at most 300 mg/day, at most 350 mg/day, at most 400 mg/day, atmost 450 mg/day, or at most 500 mg/day.

In still other aspects of this embodiment, in conjunction with amethylxanthine, an effective amount of an ACE inhibitor and/or anangiotensin II receptor antagonist disclosed herein may be, e.g., about1 mg/day to about 100 mg/day, about 1 mg/day to about 150 mg/day, about1 mg/day to about 200 mg/day, about 1 mg/day to about 250 mg/day, about1 mg/day to about 300 mg/day, about 1 mg/day to about 350 mg/day, about1 mg/day to about 400 mg/day, about 1 mg/day to about 450 mg/day, about1 mg/day to about 500 mg/day, about 10 mg/day to about 100 mg/day, about10 mg/day to about 150 mg/day, about 10 mg/day to about 200 mg/day,about 10 mg/day to about 250 mg/day, about 10 mg/day to about 300mg/day, about 10 mg/day to about 350 mg/day, about 10 mg/day to about400 mg/day, about 10 mg/day to about 450 mg/day, or about 10 mg/day toabout 500 mg/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa coughing condition may comprise a one-time administration of aneffective dose of a pharmaceutical composition disclosed herein.Alternatively, treatment of a coughing condition may comprise multipleadministrations of an effective dose of a pharmaceutical compositioncarried out over a range of time periods, such as, e.g., once daily,twice daily, trice daily, once every few days, or once weekly. Thetiming of administration can vary from individual to individual,depending upon such factors as the severity of an individual's symptoms.For example, an effective dose of a pharmaceutical composition disclosedherein can be administered to an individual once daily for an indefiniteperiod of time, or until the individual no longer requires therapy. Aperson of ordinary skill in the art will recognize that the condition ofthe individual can be monitored throughout the course of treatment andthat the effective amount of a pharmaceutical composition disclosedherein that is administered can be adjusted accordingly.

Various routes of administration can be useful for administering atherapeutic compound disclosed herein, according to a method of treatinga coughing condition disclosed herein. A pharmaceutical composition maybe administered to an individual by any of a variety of means depending,e.g., on the type of coughing condition to be treated, the location ofcoughing condition to be treated, the specific therapeutic compound orcomposition used, or other compound to be included in the composition,and the history, risk factors and symptoms of the individual. As such,topical, enteral or parenteral routes of administration may be suitablefor of treating a coughing condition disclosed herein and such routesinclude both local and systemic delivery of a therapeutic compound orcomposition disclosed herein. Compositions comprising either a singletherapeutic compound disclosed herein, or two or more therapeuticcompounds disclosed herein are intended for inhaled, topical,intranasal, sublingual, intravenous, rectal and/or vaginal use may beprepared according to any method known to the art for the manufacture ofpharmaceutical compositions.

A pharmaceutical composition disclosed herein can be administered to anindividual in a single formulation or in separate formulations, forcombined, simultaneous or sequential administration. In one embodiment,an individual is administered a first composition comprising amethylxanthine and a second composition comprising another therapeuticcompound having antitussive activity. In aspects of this embodiment, anindividual is administered a first composition comprising at least onemethylxanthine and a second composition comprising at least one othertherapeutic compound having antitussive activity. In aspects of thisembodiment, the at least one other therapeutic compound havingantitussive activity includes, without limitation, a non-opiateantitussive, an opiate antitussive, a decongestant, an expectorant, amucolytic agent, an anti-histamine, a non-steroidal anti-inflammatorydrug (NSAID), a neuropathic pain agent, a terpene, an ace inhibitor,and/or an angiotensin II receptor antagonist.

In another embodiment, an individual is administered a compositioncomprising a methylxanthine and another therapeutic compound havingantitussive activity. In aspects of this embodiment, an individual isadministered a composition comprising at least one methylxanthine and atleast one other therapeutic compound having antitussive activity. Inaspects of this embodiment, the at least one other therapeutic compoundhaving antitussive activity includes, without limitation, a non-opiateantitussive, an opiate antitussive, a decongestant, an expectorant, amucolytic agent, an anti-histamine, a non-steroidal anti-inflammatorydrug (NSAID), a neuropathic pain agent, a terpene, an ace inhibitor,and/or an angiotensin II receptor antagonist.

A pharmaceutical composition disclosed herein can also be administeredto an individual in combination with other therapeutic compounds toincrease the overall therapeutic effect of the treatment. The use ofmultiple compounds to treat an indication can increase the beneficialeffects while reducing the presence of side effects.

In an aspect of this embodiment, β₂-agonists, such as, e.g. salbutamol,salmeterol and formoterol, may be formulated for co-administration witha therapeutic compound or composition disclosed herein. In anotheraspect of this embodiment, anti-muscarinic compounds, such as, e.g.,ipratropium (e.g. ipratropium bromide) or tiotropium may be formulatedfor co-administration with a therapeutic compound or compositiondisclosed herein. In yet another aspect of this embodiment, steroids,such as, e.g., beclomethasone, dipropionate and fluticasone may beformulated for co-administration with a therapeutic compound orcomposition disclosed herein. In still another aspect of thisembodiment, matrix metalloproteinase inhibitors, leukotrienes,antibiotics, anti-infective agents, antineoplastics, peptides,antitussives, nicotine, PDE4 inhibitors, elastase inhibitors and/orsodium cromoglycate may be formulated for co-administration with atherapeutic compound or composition disclosed herein.

Aspects of the present specification may also be described as follows:

-   -   1. A composition comprising a methylxanthine or a cocoa and a        plurality of additional therapeutic agent having antitusive        activity.    -   2. The composition according to embodiment 1, wherein the        methylxanthine includes Aminophylline, Caffeine, IBMX,        Paraxanthine, Pentoxifylline, Theobromine, Theophylline,        Xanthine, or any combination thereof.    -   3. The composition according to embodiment 1 or 2, wherein the        plurality of therapeutic agent having antitusive activity        includes a non-opiate antitussive agent, an opiate antitussive        agent, a decongestant, an expectorant, a mucolytic agent, an        anti-histamine, a non-steroidal anti-inflammatory drug (NSAID),        a neuropathic pain agent, a terpene, an ACE inhibitor, an        angiotensin II receptor antagonist or any combination thereof.    -   4. The composition according to embodiment 3, wherein the        non-opiate antitussive agent includes Benproperine, Benzonate,        Bibenzonium, Butamirate, Cloperastine, Clofedanol,        Dextromethorphan, Dibunate, Dimemorfan, Dropropizine, Fedrilate,        Indantadol, Isoaminile, Morclofone, Meprotixol, Nepinalone,        Oxolamine, Oxeladin, Piperidione, Pentoxyverine, Prenoxdiazine,        Zipeprol. or any combination thereof.    -   5. The composition according to embodiment 3, wherein the opiate        antitussive agent includes Alfentanil, Alphamethylfentanyl,        Buprenorphine, Carfentanyl, Codeine, Diamorphine,        Dihydrocodeine, Ethyl Morphine, Etorphine, Fentanyl,        Hydrocodone, Hydromorphone, Loperamide, Morphine, Noscapine,        Oripavine, Oxymorphone, Oxycodone, Papaverine, Pentazocine,        Pethidine, Propoxyphene, Remifentanil, Sufentanil, Thebaine,        Tipepidine, Tramadol, or any combination thereof.    -   6. The composition according to embodiment 3, wherein the        decongestant includes Ephedrine, Levmetamfetamine, Naphazoline,        Oxymetazoline, Phenylephrine, Phenylpropanolamine,        Propylhexedrine, Pseudoephedrine, Synephrine, Tetrahydrozoline,        or any combination thereof.    -   7. The composition according to embodiment 3, wherein the        expectorant includes Ambroxol, Ammonium Bicarbonate, Ammonium        Carbonate, Bromhexine, Calcium Iodide, Carbocysteine, Guaiacol,        Guaicacol Benzoate, Guaiacol Carbonate, Guaiacol Phosphate,        Guaifenesin, Guaithylline, Hydriodic Acid, Iodinated Glycerol,        Potassium Guaiacolsulfonate, Potassium Iodide, Sodium Citrate,        Sodium Iodide, Storax Terebene, Terpin, Trifolium, Althea Root,        Antimony Pentasulfide, Creosote, Ipecacuanha (Syrup of Ipecac),        Levoverbenone, Senega, Tyloxapol, or any combination thereof.    -   8. The composition according to embodiment 3, wherein the        mucolytic agent includes Acetylcysteine, Bromhexine,        Carbocysteine, Domiodol, Erdostine, Letostine, Lysozyme,        Mecysteine Hydrochloride, Mesna, Sobrerol, Stepronin, Tiopronin,        Tyloxapol, Ambroxol, Ammonium Chloride, Dornase Alfa,        Eprazinone, Erdosteine, Letosteine, Neltenexine, or any        combination thereof.    -   9. The composition according to embodiment 3, wherein the        anti-histamine includes Acrivastine, Alimemazine, Astemizole,        Azatadine, Bromodiphenhydramine, Brompheniramine, Carbinoxamine,        Cetirizine, Chlorpheniramine, Clemastine, Cyproheptadine,        Desloratadine, Dexchlorpheniramine, Dextrobrompheniramine,        Dimenhydrinate, Diphenhydramine, Doxylamine, Fexofenadine,        Hydroxyzine, Levocetirizine, Loratadine, Meclizine, Mizolastine,        Quetiapine, Pheniramine, Promethazine, Pyrilamine,        Tripelennamine, Triprolidine., or any combination thereof.    -   10. The composition according to embodiment 3, wherein the NSAID        includes a salicylate derivative NSAID, a p-amino phenol        derivative NSAID, a propionic acid derivative NSAID, an acetic        acid derivative NSAID, an enolic acid derivative NSAID, a        fenamic acid derivative NSAID, a non-selective cyclo-oxygenase        (COX) inhibitor, a selective cyclooxygenase 1 (COX 1) inhibitor,        a selective cyclooxygenase 2 (COX 2) inhibitor, or any        combination thereof.    -   11. The composition according to embodiment 3, wherein the        neuropathic pain agent includes Acetazolamide, Amitriptyline,        Amitriptylinoxide, Baclofen, Butriptyline, Carbamazepine,        Carisoprodol, Clobazam, Clomipramine, Conotoxins,        Cyclobenzaprine, Demexiptiline, Desipramine, Diazepam,        Dibenzepin, Dimetacrine, Doxepin, Duloexetine, Ethotoin,        Felbamate, Fosphenytoin, Gabapentin, Imipramine, Imipraminoxide,        Ketamine, Lamotrigine, Lidocaine, Lignocaine, Lofepramine,        Mephenytoin, Melitracen, Metapramine, Metaxalone, Methadone,        Methocarbamol, Nitroxazepine, Nortriptyline, Noxiptiline,        Oxcarbazepine, Phenobarbital, Phensuximide, Phenytoin,        Pipofezine, Pregabalin, Progabide, Propizepine, Protriptyline,        Quinupramine, Stiripentol, Tiagabine, Topiramate, Trimethadione,        Valproate, Venlafaxine, Vigabatrin, Zonisamide, or any        combination thereof.    -   12. The composition according to embodiment 3, wherein the        terpene includes camphor oil, citronella, clove oil, eucalyptus        oil, ginger oil, horsemint oil, I-menthol, lemon oil, limonene,        marjoram oil, mint oil, neroli oil, peppermint oil, pine oil,        rose oil, rosemary oil, spearmint oil, tea tree oil, thyme oil,        water mint oil, or any combination thereof.    -   13. The composition according to embodiment 3, wherein the ACE        inhibitor includes Captopril, Enalapril, Lisinopril, Meleate,        Ramipril, or any combination thereof.    -   14. The composition according to embodiment 3, wherein the        angiotensin II receptor antagonist includes Azilsartan,        Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan,        Telmisartan, Valsartan, or any combination thereof.    -   15. The composition according to embodiments 1-3, wherein the        plurality of therapeutic compounds does not include a non-opiate        antitussive agent.    -   16. The composition according to embodiments 1-4, wherein the        plurality of therapeutic compounds does not include        Dextromethorphan.    -   17. The composition according to embodiments 1-3, wherein the        plurality of therapeutic compounds does not include an        anti-histamine.    -   18. The composition according to embodiments 1-3 or 9, wherein        the plurality of therapeutic compounds does not include        Azatadine, Bromodiphenhydramine, Brompheniramine, Carbinoxamine,        Cetirizine, Chlorpheniramine, Clemestine, Dexchlorpheniramine,        Dexbrompheniramine, Diphenhydramine, Doxylamine, Pyrilamine,        Tripelennamine, or Tripolidine.    -   19. The composition according to embodiments 1-18, wherein the        pharmaceutical composition reduces an unwanted side.    -   20. The composition according to embodiment 19, wherein the        unwanted side includes sedation, cognitive fogging, dizziness,        drowsiness, postural hypertension, coordination problems,        weakness, tremors, respiratory depression, psychotropic effects,        sleep disturbances, unwanted waitfulness, CNS stimulation,        weight gain, appetite change, change in sexual function,        constipation, dry mouth, gut erosion, gastric ulcerations, renal        inflammation, cardiovascular hypertension, cardiovascular        stimulation, hyperchlimina, not going into public, chest pain,        stress incontinence, or any combination thereof.    -   21. The composition according to embodiments 1-20, wherein the        antitussive activity reduces a symptom associated with a        coughing condition.    -   22. The composition according to embodiment 21, wherein the        antitussive activity reduces a symptom associated with a        coughing condition by at least 10%, at least 15%, at least 20%,        at least 25%, at least 30%, at least 35%, at least 40%, at least        45%, at least 50%, at least 55%, at least 60%, at least 65%, at        least 70%, at least 75%, at least 80%, at least 85%, at least        90%, or at least 95%.    -   23. The composition according to embodiment 21, wherein the        symptom includes the frequency of a cough, the severity of a        cough, the volume or noise level of a cough, hoarseness, sore        throat, breathing difficulty, respiratory congestion, wheezing,        respiratory constriction, respiratory inflammation, muscle        spasms associated with a cough, phlegm production, fainting,        insomnia, vomiting, subconjunctival hemorrhage (red eye), cough        defecation, cough urination, abdominal hernia, pelvic hernia,        costochondritis, or lower rib fracture.    -   24. The composition according to embodiments 1-23, wherein the        antitussive activity suppresses a vagal nerve function        associated with a cough.    -   25. The composition according to embodiment 24, wherein the        antitussive activity suppresses a vagal nerve function        associated with a cough by at least 10%, at least 15%, at least        20%, at least 25%, at least 30%, at least 35%, at least 40%, at        least 45%, at least 50%, at least 55%, at least 60%, at least        65%, at least 70%, at least 75%, at least 80%, at least 85%, at        least 90%, or at least 95%.    -   26. The composition according to embodiments 1-25, wherein the        antitussive activity suppresses a central nerve function        associated with a cough.    -   27. The composition according to embodiment 26, wherein the        antitussive activity suppresses a central nerve function        associated with a cough by at least 10%, at least 15%, at least        20%, at least 25%, at least 30%, at least 35%, at least 40%, at        least 45%, at least 50%, at least 55%, at least 60%, at least        65%, at least 70%, at least 75%, at least 80%, at least 85%, at        least 90%, or at least 95%.    -   28. The composition according to embodiments 1-27, wherein the        antitussive activity suppresses a peripheral nerve function        associated with a cough.    -   29. The composition according to embodiment 28, wherein the        antitussive activity suppresses a peripheral nerve function        associated with a cough by at least 10%, at least 15%, at least        20%, at least 25%, at least 30%, at least 35%, at least 40%, at        least 45%, at least 50%, at least 55%, at least 60%, at least        65%, at least 70%, at least 75%, at least 80%, at least 85%, at        least 90%, or at least 95%.    -   30. The composition according to embodiments 1-29, wherein the        composition is formulated for inhalatory administration.    -   31. The composition according to embodiments 1-29, wherein the        composition is formulated for oral administration.    -   32. The composition according to embodiments 1-3 or 17-31,        wherein the composition includes a methylxanthine and a        non-opiate antitussive agent.    -   33. The composition according to embodiment 32, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 1 mg/mL to about 250 mg/mL of the        non-opiate antitussive agent.    -   34. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and an opiate        antitussive agent.    -   35. The composition according to embodiment 34, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 75 mg/mL of the        opiate antitussive agent.    -   36. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and a        decongestant.    -   37. The composition according to embodiment 36, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 6000 mg/mL of the        decongestant.    -   38. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and an        expectorant.    -   39. The composition according to embodiment 38, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 6000 mg/mL of the        expectorant.    -   40. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and a        mucolytic agent.    -   41. The composition according to embodiment 40, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 6000 mg/mL of the        mucolytic agent.    -   42. The composition according to embodiments 1-3, 15, 16, or        19-31, wherein the composition includes a methylxanthine and an        anti-histamine.    -   43. The composition according to embodiment 42, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 100 mg/mL of the        anti-histamine.    -   44. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and a NSAID.    -   45. The composition according to embodiment 44, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 1 mg/mL to about 3200 mg/mL of the        NSAID.    -   46. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and a        neuropathic pain agent.    -   47. The composition according to embodiment 46, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 8000 mg/mL of the        neuropathic pain agent.    -   48. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and a terpene.    -   49. The composition according to embodiments 48, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.01 mg/mL to about 200 mg/mL of the        terpene.    -   50. The composition according to embodiments 1-3 or 15-31,        wherein the composition includes a methylxanthine and an ACE        inhibitor.    -   51. The composition according to embodiment 50, wherein the        composition includes about 1 mg/mL to about 1000 mg/mL of the        methylxanthine and about 0.1 mg/mL to about 450 mg/mL of the ACE        inhibitor.    -   52. The composition of claim 1, wherein the composition includes        a methylxanthine and an angiotensin II receptor antagonist.    -   53. The composition of claim 46, wherein the composition        includes about 1 mg/mL to about 1000 mg/mL of the methylxanthine        and about 0.1 mg/mL to about 450 mg/mL of the angiotensin II        receptor antagonist.    -   54. A method of treating a coughing condition in an individual,        the method comprising the step of administering a composition        according to embodiments 1-53, wherein administration reduces a        symptom associated with the coughing condition.    -   55. The method according to embodiment 54, wherein the coughing        condition comprises an acute coughing condition.    -   56. The method according to embodiment 54, wherein the coughing        condition comprises a subacute coughing condition.    -   57. The method according to embodiment 54, wherein the coughing        condition comprises a chronic coughing condition.    -   58. The method according to embodiments 54-57, wherein the        coughing condition comprises a non-productive coughing        condition.    -   59. The method according to embodiments 54-57, wherein the        coughing condition comprises a productive coughing condition.    -   60. The method according to embodiments 54-59, wherein the        coughing condition comprises a cough associated with a disease        or disorder.    -   61. The method according to embodiment 60, wherein the disease        or disorder is an asthma, an atopic cough a bronchitis, a        gastroesophageal reflux disease (GERD), an infection of the        respiratory tract, an inflammation, a medication, a pollutant, a        post-nasal drip, a smoking event, a vagal nerve irritation, a        diseases of the external auditory canal, a lung disease, a lung        tumor, a habit cough, a tic, a Tourette syndrome, a        cardiovascular disease, or a post-infectious cough.    -   62. The method according to embodiment 61, wherein the lung        disease includes a bronchiectasis, a cystic fibrosis, an        interstitial lung disease, a sarcoidosis, or a COPD.    -   63. The method according to embodiment 61, wherein the        cardiovascular disease includes a heart failure, a pulmonary        infarction, or an aortic aneurysm.    -   64. The method according to embodiment 61, wherein the infection        of the respiratory tract includes a cold, croup, pertussis,        pneumonia, or tuberculosis.    -   65. The method according to embodiments 54-64, wherein        administration of the pharmaceutical composition reduces an        unwanted side.    -   66. The method according to embodiment 65, wherein the unwanted        side includes sedation, cognitive fogging, dizziness,        drowsiness, postural hypertension, coordination problems,        weakness, tremors, respiratory depression, psychotropic effects,        sleep disturbances, unwanted waitfulness, CNS stimulation,        weight gain, appetite change, change in sexual function,        constipation, dry mouth, gut erosion, gastric ulcerations, renal        inflammation, cardiovascular hypertension, cardiovascular        stimulation, hyperchlimina, not going into public, chest pain,        stress incontinence, or any combination thereof.    -   67. The method according to embodiments 54-66, wherein the        symptom includes coughing, hoarseness, sore throat, breathing        difficulty, respiratory congestion, wheezing, respiratory        constriction, respiratory inflammation, muscle spasms associated        with a cough, phlegm production, fainting, insomnia, vomiting,        subconjunctival hemorrhage (red eye), cough defecation, cough        urination, abdominal hernia, pelvic hernia, costochondritis,        lower rib fracture, or any combination thereof.    -   68. Use of a composition according to embodiments 1-53 in the        manufacture of a medicament for the treatment of a coughing        condition.    -   69. Use of a composition according to embodiments 1-53 in the        treatment of a coughing condition.    -   70. The use according to embodiment 67 or 68, wherein the        coughing condition comprises an acute coughing condition.    -   71. The use according to embodiment 67 or 68, wherein the        coughing condition comprises a subacute coughing condition.    -   72. The use according to embodiment 67 or 68, wherein the        coughing condition comprises a chronic coughing condition.    -   73. The use according to embodiments 67-72, wherein the coughing        condition comprises a non-productive coughing condition.    -   74. The use according to embodiments 67-72, wherein the coughing        condition comprises a productive coughing condition.    -   75. The use according to embodiments 67-74, wherein the coughing        condition comprises a cough associated with a disease or        disorder.    -   76. The use according to embodiment 75, wherein the disease or        disorder is an asthma, an atopic cough a bronchitis, a        gastroesophageal reflux disease (GERD), an infection of the        respiratory tract, an inflammation, a medication, a pollutant, a        post-nasal drip, a smoking event, a vagal nerve irritation, a        diseases of the external auditory canal, a lung disease, a lung        tumor, a habit cough, a tic, a Tourette syndrome, a        cardiovascular disease, or a post-infectious cough.    -   77. The use according to embodiment 76, wherein the lung disease        includes a bronchiectasis, a cystic fibrosis, an interstitial        lung disease, a sarcoidosis, or a COPD.    -   78. The use according to embodiment 76, wherein the        cardiovascular disease includes a heart failure, a pulmonary        infarction, or an aortic aneurysm.    -   79. The use according to embodiment 76, wherein the infection of        the respiratory tract includes a cold, croup, pertussis,        pneumonia, or tuberculosis.    -   80. The use according to embodiments 67-79, wherein        administration of the pharmaceutical composition reduces an        unwanted side.    -   81. The use according to embodiment 80, wherein the unwanted        side includes sedation, cognitive fogging, dizziness,        drowsiness, postural hypertension, coordination problems,        weakness, tremors, respiratory depression, psychotropic effects,        sleep disturbances, unwanted waitfulness, CNS stimulation,        weight gain, appetite change, change in sexual function,        constipation, dry mouth, gut erosion, gastric ulcerations, renal        inflammation, cardiovascular hypertension, cardiovascular        stimulation, hyperchlimina, not going into public, chest pain,        stress incontinence, or any combination thereof.    -   82. The use according to embodiment 80, wherein the symptom        includes coughing, hoarseness, sore throat, breathing        difficulty, respiratory congestion, wheezing, respiratory        constriction, respiratory inflammation, muscle spasms associated        with a cough, phlegm production, fainting, insomnia, vomiting,        subconjunctival hemorrhage (red eye), cough defecation, cough        urination, abdominal hernia, pelvic hernia, costochondritis,        lower rib fracture, or any combination thereof.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the compounds,pharmaceutical compositions, or methods or uses of treating a coughingcondition.

Example 1 Oral Administration of Theobromine

This example illustrates the antitussive activity of theobromine.

Nine male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) were randomly allocated equally into one of three groups. Group 1animals were administered vehicle only; Group 2 animals were orallydosed (volume 2 mL/kg) with 3 mg/kg of theobromine; Group 3 animals wereorally dosed with 7 mg/kg of theobromine. All pre-treatments wereadministered 120 minutes prior to citric acid exposure. Individualguinea pigs were placed in an exposure chamber with an airflow of 2L/min for 10 minutes prior to citric acid exposure to allowacclimatisation. Cough responses were induced by exposure to 1 M citricacid aerosol generated by an ultrasonic nebuliser at a nebulisation rateof 0.6 mL/min for 10 minutes. Coughs were counted throughout the 10minute citric acid exposure and for a further 5 minute post-exposurerecovery period.

The results of this study are shown in Table 1. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 28±3 coughs with a mean onset time for first cough of66±18 seconds. In theobromine-treated animals there was a dose dependantdecrease in the total number of coughs evoked by citric acid exposure aswell as an increase in the onset time to the first cough. At the highestdose, the total number of coughs had been reduced to 18±3, while theonset to the first cough had been extended to 98±36 seconds.

TABLE 1 Cough Suppression of Theobromine Cough Events Group¹ TreatmentMean Number Mean Onset Time Group 1 vehicle (p.o.) 28 ± 3 66 ± 18 secGroup 2 3 mg/kg theobromine (p.o.) 25 ± 4 73 ± 17 sec Group 3 7 mg/kgtheobromine (p.o.) 18 ± 3 98 ± 36 sec ¹n = 3 guinea pigs per group.

Example 2 Oral and Intratracheal Administration of Theobromine

This example illustrates the antitussive activity of theobromine.

Thirty-six male Dunkin Hartley guinea pigs (350-550 g, supplied byHarlan UK Ltd) were randomly allocated equally into one of six groups.Group 1 animals were administered vehicle only; Group 2 animals wereintra-peronteneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals were orally dosed (volume 2 mL/kg) with 30 mg/kg oftheobromine; Group 4 animals were intra-tracheally dosed with 3 mg/kg oftheobromine; Group 5 animals were intra-tracheally dosed with 10 mg/kgof theobromine; and Group 6 animals were intra-tracheally dosed with 30mg/kg of theobromine. All pre-treatments were administered 30 minutesprior to citric acid exposure. Individual guinea pigs were placed in anexposure chamber with an airflow of 2 L/min for 10 minutes prior tocitric acid exposure to allow acclimatisation. Cough responses wereinduced by exposure to 1 M citric acid aerosol generated by anultrasonic nebuliser at a nebulisation rate of 0.6 mL/min for 10minutes. Coughs were counted throughout the 10 minute citric acidexposure and for a further 5 minute post-exposure recovery period.

The results of this study are shown in Table 2. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 26±4 coughs with a mean onset time for first cough of71±26 seconds. The level of response was significantly reduced to 5±1coughs in codeine-treated animals and the onset to the first cough wassignificantly extended to 337±51 seconds. Pre-treatment with theobromine(30 mg/kg, p.o.) also caused a significant reduction to the number ofcitric acid induced coughs (12±2), although the onset of the first coughwas not significantly increased when compared to the control animals(126±20 seconds c.f. 71±26 seconds). Local administration (i.t.) oftheobromine also had a significant dose dependant effect on the totalnumber of coughs, reducing the number of coughs at a dose of 30 mg/kg oftheobromine to 6±1. Indeed at the doses of 10 mg/kg (i.t.) theobrominecaused a similar degree of cough suppression to that observed at 30mg/kg (p.o.) theobromine (10.3±2 c.f. 12±2). It was also evident withincreasing concentration of intra-tracheally administered theobromine,that there was an increase to the onset of the first cough which wassignificantly increased with a dose of 30 mg/kg to 210±22 seconds.

TABLE 2 Cough Suppression of Theobromine Cough Events Mean Onset Group¹Treatment Mean Number Time Group 1 vehicle (p.o.) 26 ± 4   71 ± 26 secGroup 2 25 mg/kg codeine (i.p.)  5 ± 1** 337 ± 51 sec Group 3 30 mg/kgtheobromine (p.o.) 12 ± 2** 126 ± 20 sec Group 4  3 mg/kg theobromine(i.t.) 17 ± 2*  115 ± 29 sec Group 5 10 mg/kg theobromine (i.t.) 10 ±2** 134 ± 18 sec Group 6 30 mg/kg theobromine (i.t.)  6 ± 1**  210 ± 22sec* ¹n = 6 guinea pigs per group. **P < 0.01. *P < 0.05.

Example 3 Theobromine and a Non-Opiate Antitussive Agent

This example illustrates the antitussive activity of theobromine incombination with a non-opiate antitussive agent.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) were randomly allocated equally into one of five groups. Group 1animals were administered vehicle only; Group 2 animals wereintra-peronteneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals were orally dosed (volume 2 mL/kg) with 10 mg/kg oftheobromine; Group 4 animals were orally dosed with 10 mg/kg oftheobromine and 10 mg/kg dextromethophan; and Group 5 animals wereorally dosed with 10 mg/kg of theobromine and 30 mg/kg dextromethophan.Pre-treatments with theobromine were administered 120 minutes prior tocitric acid exposure, whereas pre-treatments with dextromethophan orvehicle were administered 60 minutes prior to citric acid exposure.Pre-treatments with codeine were administered 30 minutes prior to citricacid exposure. Individual guinea pigs were placed in an exposure chamberwith an airflow of 2 L/min for 10 minutes prior to citric acid exposureto allow acclimatisation. Cough responses were induced by exposure to 1M citric acid aerosol generated by an ultrasonic nebuliser at anebulisation rate of 0.6 mL/min for 10 minutes. Coughs were countedthroughout the 10 minute citric acid exposure and for a further 5 minutepost-exposure recovery period.

The results of this study are shown in Table 3. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 28±5 coughs with a mean onset time for first cough of52±9 seconds. The level of response was significantly reduced to 7±2coughs in codeine-treated animals and the onset to the first cough wassignificantly extended to 170±32 seconds. Pre-treatment with theobromine(10 mg/kg) also caused a significant reduction to the number of citricacid induced coughs (13±2), as well as an increase duration to the onsetof the first cough (139±22 seconds). In combination with dextromethophan(10 mg/kg or 30 mg/kg), the inhibitory effect of theobromine on thecitric acid-induced tussive activity was potentiated slightly with thehigher dose both in respect to the total number of coughs (11±2 c.f.13±2) and the onset time to the first cough (146±23 seconds c.f. 139±22seconds).

TABLE 3 Cough Suppression of Theobromine and Non-Opiate AntitussiveAgent Cough Events Mean Onset Group¹ Treatment Mean Number Time Group 1vehicle (p.o.) 28 ± 5   52 ± 9 sec Group 2 25 mg/kg codeine (i.p.)  7 ±2** 170 ± 32 sec** Group 3 10 mg/kg theobromine (p.o.) 13 ± 2** 139 ± 22sec* Group 4 10 mg/kg theobromine (p.o.) 15 ± 3*  115 ± 14 sec 10 mg/kgdextromethophan (p.o.) Group 5 10 mg/kg theobromine (p.o.) 11 ± 2** 146± 23 sec* 30 mg/kg dextromethophan (p.o.) ¹n = 6 guinea pigs per group.**P < 0.01. *P < 0.05.

Example 4 Theobromine and an Opiate Antitussive Agent

This example illustrates the antitussive activity of theobromine incombination with an opiate antitussive agent.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) were randomly allocated equally into one of five groups. Group 1animals were administered vehicle only; Group 2 animals wereintra-peronteneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals were orally dosed (volume 2 mL/kg) with 7 mg/kg oftheobromine; Group 4 animals were orally dosed with 7 mg/kg oftheobromine and 8 mg/kg codeine; and Group 5 animals were orally dosedwith 7 mg/kg of theobromine and 16 mg/kg codeine. Pre-treatments withtheobromine were administered 120 minutes prior to citric acid exposure,whereas oral pre-treatments with codeine were administered 60 minutesprior to citric acid exposure. Intraperitoneal pre-treatments withcodeine were administered 30 minutes prior to citric acid exposure.Vehicle animals were dosed at both 120 minutes and 60 minutes prior tocitric acid exposure. Individual guinea pigs were placed in an exposurechamber with an airflow of 2 L/min for 10 minutes prior to citric acidexposure to allow acclimatisation. Cough responses were induced byexposure to 1 M citric acid aerosol generated by an ultrasonic nebuliserat a nebulisation rate of 0.6 mL/min for 10 minutes. Coughs were countedthroughout the 10 minute citric acid exposure and for a further 5 minutepost-exposure recovery period.

The results of this study are shown in Table 4. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 27±4 coughs with a mean onset time for first cough of61±9 seconds. The level of response was significantly reduced to 6±1coughs in codeine-treated animals and the onset to the first cough wassignificantly extended to 195±33 seconds. Pre-treatment with theobromine(7 mg/kg) also caused a reduction to the number of citric acid inducedcoughs (19±3), as well as an increase in duration to the onset of thefirst cough (91±13 seconds), although when compared to vehicle controlanimals these changes were not significant. However, once combined withcodeine (8 mg/kg or 16 mg/kg), the inhibitory response of theobromine onthe citric acid induced tussive activity was dose dependentlypotentiated. Indeed in combination with the highest dose of codeine (16mg/kg) the total number of coughs were now significantly reduced to 4±1(c.f 19±3 seen in animals treated with theobromine alone), and onset tothe first cough was also significantly extended to 202±30 seconds (c.f.91±13 seconds).

TABLE 4 Cough Suppression of Theobromine and Opiate Antitussive AgentCough Events Group¹ Treatment Mean Number Mean Onset Time Group 1vehicle (p.o.) 27 ± 4  61 ± 9 sec Group 2 25 mg/kg codeine (i.p.)   6 ±1** 195 ± 33 sec** Group 3 7 mg/kg theobromine (p.o.) 19 ± 3  91 ± 13sec Group 4 7 mg/kg theobromine (p.o.)  10 ± 2** 147 ± 15 sec* 8 mg/kgcodeine (p.o.) Group 5 7 mg/kg theobromine (p.o.)   4 ± 1** 202 ± 30sec** 16 mg/kg codeine (p.o.) ¹n = 6 guinea pigs per group. **P < 0.01.*P < 0.05.

Example 5 Theobromine and a Decongestant

This example illustrates the antitussive activity of theobromine incombination with a decongestant.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) were randomly allocated equally into one of five groups. Group 1animals were administered vehicle only; Group 2 animals wereintra-peronteneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals were orally dosed (volume 2 mL/kg) with 10 mg/kg oftheobromine; Group 4 animals were orally dosed with 10 mg/kg oftheobromine and 10 mg/kg pseudoephidrine; and Group 5 animals wereorally dosed with 10 mg/kg of theobromine and 30 mg/kg pseudoephidrine.Pre-treatments with theobromine were administered 120 minutes prior tocitric acid exposure, whereas oral pre-treatments with pseudoephidrinewere administered 30 minutes prior to citric acid exposure.Intraperitoneal pre-treatments with codeine were administered 30 minutesprior to citric acid exposure. Vehicle animals were dosed at both 120minutes and 30 minutes prior to citric acid exposure. Individual guineapigs were placed in an exposure chamber with an airflow of 2 L/min for10 minutes prior to citric acid exposure to allow acclimatisation. Coughresponses were induced by exposure to 1 M citric acid aerosol generatedby an ultrasonic nebuliser at a nebulisation rate of 0.6 mL/min for 10minutes. Coughs were counted throughout the 10 minute citric acidexposure and for a further 5 minute post-exposure recovery period.

The results of this study are shown in Table 5. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 28±4 coughs with a mean onset time for first cough of72±10 seconds. The level of response was significantly reduced to 6±1coughs in codeine-treated animals and the onset to the first cough wassignificantly extended to 195±25 seconds. Pre-treatment with theobromine(10 mg/kg) also caused a significant reduction to the number of citricacid induced coughs (13±3), as well as an increase in duration to theonset of the first cough (156±15 seconds). In combination withpseudoephedrine (10 mg/kg and 30 mg/kg), the inhibitory response ofBC1036 on the citric acid induced tussive activity, was potentiatedslightly with the highest dose both in respect of total number of coughs(9±2 c.f. 13±3) and onset time to the first cough (170±15 seconds c.f.156±15 seconds).

TABLE 5 Cough Suppression of Theobromine and Decongestant Cough EventsMean Onset Group¹ Treatment Mean Number Time Group 1 vehicle (p.o.) 28 ±4   72 ± 10 sec Group 2 25 mg/kg codeine (i.p.)  6 ± 1** 195 ± 25 sec**Group 3 10 mg/kg theobromine (p.o.) 13 ± 3** 156 ± 15 sec** Group 4 10mg/kg theobromine (p.o.) 12 ± 3** 164 ± 17 sec** 10 mg/kgpseudoephidrine (p.o.) Group 5 10 mg/kg theobromine (p.o.)  9 ± 2** 170± 15 sec** 30 mg/kg pseudoephidrine (p.o.) ¹n = 6 guinea pigs per group.**P < 0.01.

Example 6 Theobromine and an Antihistamine

This example illustrates the antitussive activity of theobromine incombination with an antihistamine.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) were randomly allocated equally into one of five groups. Group 1animals were administered vehicle only; Group 2 animals wereintra-peronteneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals were orally dosed (volume 2 mL/kg) with 10 mg/kg oftheobromine; Group 4 animals were orally dosed with 10 mg/kg oftheobromine and 10 mg/kg chlorpheniramine; and Group 5 animals wereorally dosed with 10 mg/kg of theobromine and 30 mg/kg chlorpheniramine.Pre-treatments with theobromine were administered 120 minutes prior tocitric acid exposure, whereas oral pre-treatments with chlorpheniraminewere administered 30 minutes prior to citric acid exposure.Intraperitoneal pre-treatments with codeine were administered 30 minutesprior to citric acid exposure. Vehicle animals were dosed at both 120minutes and 30 minutes prior to citric acid exposure. Individual guineapigs were placed in an exposure chamber with an airflow of 2 L/min for10 minutes prior to citric acid exposure to allow acclimatisation. Coughresponses were induced by exposure to 1 M citric acid aerosol generatedby an ultrasonic nebuliser at a nebulisation rate of 0.6 mL/min for 10minutes. Coughs were counted throughout the 10 minute citric acidexposure and for a further 5 minute post-exposure recovery period.

The results of this study are shown in Table 6. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 26±4 coughs with a mean onset time for first cough of42±9 seconds. The level of response was significantly reduced to 5±1coughs in codeine-treated animals and the onset to the first cough wassignificantly extended to 236±22 seconds. Pre-treatment with theobromine(10 mg/kg) also caused a significant reduction to the number of citricacid induced coughs (15±2), as well as an increase in duration to theonset of the first cough (103±15 seconds). In combination withchlorpheniramine (0.3 mg/kg and 1 mg/kg), the inhibitory response oftheobromine on the citric acid induced tussive activity, was dosedependently potentiated. Indeed in combination with the highest dose ofchlorpheniramine (1 mg/kg) the total number of coughs was reduced to10±2 (c.f 15±2 seen in animals treated with theobromine alone), andonset to the first cough was extended to 130±11 seconds (c.f. 111±17seconds).

TABLE 6 Cough Suppression of Theobromine and Antihistamine Cough EventsMean Onset Group¹ Treatment Mean Number Time Group 1 vehicle (p.o.) 26 ±4   42 ± 9 sec Group 2 25 mg/kg codeine (i.p.)  5 ± 1** 236 ± 22 sec**Group 3 10 mg/kg theobromine (p.o.) 15 ± 2** 103 ± 15 sec* Group 4 10mg/kg theobromine (p.o.) 12 ± 2** 111 ± 17 sec* 0.3 mg/kgchlorpheniramine (p.o.) Group 5 10 mg/kg theobromine (p.o.) 10 ± 2** 130± 11 sec** 1 mg/kg chlorpheniramine (p.o.) ¹n = 6 guinea pigs per group.**P < 0.01. *P < 0.05.

Example 7 Theobromine and an Expectorant

This example illustrates the antitussive activity of theobromine incombination with an expectorant.

Twenty-four male Dunkin Hartley guinea pigs (400-510 g, supplied byHarlan UK Ltd) were randomly allocated equally into one of four groups.Group 1 animals were administered vehicle only; Group 2 animals wereorally dosed (volume 2 mL/kg) with 10 mg/kg of theobromine; Group 3animals were orally dosed (volume 2 mL/kg) with 30 mg/kg guaifenesin;and Group 4 animals were orally dosed with 10 mg/kg of theobromine and30 mg/kg guaifenesin. Pre-treatments with theobromine were administered30 minutes prior to citric acid exposure, whereas pre-treatments withguaifenesin or vehicle were administered 60 minutes prior to citric acidexposure. Individual guinea pigs were placed in an exposure chamber withan airflow of 2 L/min for 10 minutes prior to citric acid exposure toallow acclimatisation. Cough responses were induced by exposure to 1 Mcitric acid aerosol generated by an ultrasonic nebuliser at anebulisation rate of 0.6 mL/min for 10 minutes. Coughs were countedthroughout the 10 minute citric acid exposure and for a further 5 minutepost-exposure recovery period.

The results of this study are shown in Table 7. The mean number ofcitric acid induced cough responses recorded in the vehicle treatedguinea pigs was 30±4 coughs with a mean onset time for first cough of46±10 seconds. Pre-treatment with theobromine (10 mg/kg, p.o.) caused asignificant (P<0.05) reduction to the number of citric acid inducedcoughs (15±3), as well as an increase duration to the onset of the firstcough (126±12 seconds). In contrast, guaifenesin (30 mg/kg, p.o.) had nosignificant effect on the total number of coughs (28±3) evoked by citricacid exposure or on the onset of the first cough (52±10 seconds). Incombination with guaifenesin (30 mg/kg, p.o.), the inhibitory effect oftheobromine on the citric acid-induced tussive activity, showed a trendto be potentiated in respect to total number of coughs observed (13±3c.f. 15±3), although such trend was not evident with regard to onset ofthe first cough (121±10 seconds c.f. 126±12 seconds).

TABLE 7 Cough Suppression of Theobromine and Expectorant Cough EventsMean Mean Onset Group¹ Treatment Number Time Group 1 vehicle (p.o.) 30 ±4 46 ± 10 sec Group 2 10 mg/kg theobromine (p.o.) 15 ± 3**  126 ± 12sec** Group 3 30 mg/kg guaifenesin (p.o.) 28 ± 3 52 ± 10 sec Group 4 10mg/kg theobromine (p.o.) 13 ± 3**  121 ± 10 sec** 30 mg/kg guaifenesin(p.o.) ¹n = 6 guinea pigs per group. **P < 0.01.

Example 8 Theobromine and a NSAID

This example illustrates the antitussive activity of theobromine incombination with a NSAID.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) are randomly allocated equally into one of five groups. Group 1animals are administered vehicle only; Group 2 animals areintra-peritoneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals are orally dosed (volume 2 mL/kg) with 10 mg/kg oftheobromine; Group 4 animals are orally dosed with 10 mg/kg oftheobromine and 10 mg/kg ibuprofen; and Group 5 animals are orally dosedwith 10 mg/kg of theobromine and 30 mg/kg ibuprofen; Group 6 animals areorally doses with 30 mg/kg of ibuprofen only. Pre-treatments withtheobromine are administered 120 minutes prior to citric acid exposure,whereas pre-treatments with ibuprofen or vehicle are administered 60minutes prior to citric acid exposure. Pre-treatments with codeine areadministered 30 minutes prior to citric acid exposure. Individual guineapigs are placed in an exposure chamber with an airflow of 2 L/min for 10minutes prior to citric acid exposure to allow acclimatisation. Coughresponses are induced by exposure to 1 M citric acid aerosol generatedby an ultrasonic nebuliser at a nebulisation rate of 0.6 mL/min for 10minutes. Coughs are counted throughout the 10 minute citric acidexposure and for a further 5 minute post-exposure recovery period.

The mean number of citric acid induced cough responses recorded in thevehicle treated guinea pigs is 30±5 coughs with a mean onset time forfirst cough of 55±7 seconds. The level of response is significantlyreduced to 8±3 coughs in codeine-treated animals and the onset to thefirst cough was significantly extended to 150±32 seconds. Pre-treatmentwith theobromine (10 mg/kg) also caused a significant reduction to thenumber of citric acid induced coughs (15±3), as well as small increaseduration to the onset of the first cough (113±15 seconds). Incombination with both doses of ibuprofen (10 mg/kg or 30 mg/kg), theinhibitory effect of theobromine on the citric acid-induced tussiveactivity was potentiated substantially with both the lower and higherdoses both in respect to the total number of coughs (11±2 c.f. 9±1) andthe onset time to the first cough (143±19 seconds c.f. 122±20 seconds).Ibuprofen on its own has very little effect on total number of coughs(22±6) or on the onset time to the first cough (70±5 seconds).

Example 9 Theobromine and an Neuropathic Pain Agent

This example illustrates the antitussive activity of theobromine incombination with an neuropathic pain agent.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) are randomly allocated equally into one of five groups. Group 1animals are administered vehicle only; Group 2 animals areintra-peritoneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals are orally dosed (volume 2 mL/kg) with 10 mg/kg oftheobromine; Group 4 animals are orally dosed with 10 mg/kg oftheobromine and 30 mg/kg gabapentin; and Group 5 animals are orallydosed with 10 mg/kg of theobromine and 60 mg/kg gabapentin; Group 6animals are orally doses with 60 mg/kg of gabapentin only.Pre-treatments with theobromine are administered 120 minutes prior tocitric acid exposure, whereas pre-treatments with gabapentin or vehicleare administered 60 minutes prior to citric acid exposure.Pre-treatments with codeine are administered 30 minutes prior to citricacid exposure. Individual guinea pigs are placed in an exposure chamberwith an airflow of 2 L/min for 10 minutes prior to citric acid exposureto allow acclimatisation. Cough responses are induced by exposure to 1 Mcitric acid aerosol generated by an ultrasonic nebuliser at anebulisation rate of 0.6 mL/min for 10 minutes. Coughs are countedthroughout the 10 minute citric acid exposure and for a further 5 minutepost-exposure recovery period.

The mean number of citric acid induced cough responses recorded in thevehicle treated guinea pigs is 31±6 coughs with a mean onset time forfirst cough of 58±9 seconds. The level of response is significantlyreduced to 9±4 coughs in codeine-treated animals and the onset to thefirst cough was significantly extended to 161±31 seconds. Pre-treatmentwith theobromine (10 mg/kg) also caused a significant reduction to thenumber of citric acid induced coughs (14±4), as well as small increaseduration to the onset of the first cough (108±19 seconds). Incombination with gabapentin (30 mg/kg or 60 mg/kg), the inhibitoryeffect of theobromine on the citric acid-induced tussive activity waspotentiated significantly with the higher dose both in respect to thetotal number of coughs (13±2 c.f. 6±2) and the onset time to the firstcough (89±20 seconds c.f. 142±18 seconds). Gabapentin on its own hasvery little effect on total number of coughs (24±8) or on the onset timeto the first cough (90±6 seconds).

Example 10 Theobromine and a Terpene

This example illustrates the antitussive activity of theobromine incombination with a terpene.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) are randomly allocated equally into one of five groups. Group 1animals are administered vehicle only; Group 2 animals areintra-peritoneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals are orally dosed (volume 2 mL/kg) with 10 mg/kg oftheobromine; Group 4 animals are orally dosed with 10 mg/kg oftheobromine and 0.3 mg/kg peppermint oil; and Group 5 animals are orallydosed with 10 mg/kg of theobromine and 1 mg/kg ibuprofen; Group 6animals are orally doses with 1 mg/kg of peppermint oil only.Pre-treatments with theobromine and peppermint oil are administered 120minutes prior to citric acid exposure. Pre-treatments with codeine areadministered 30 minutes prior to citric acid exposure. Individual guineapigs are placed in an exposure chamber with an airflow of 2 L/min for 10minutes prior to citric acid exposure to allow acclimatisation. Coughresponses are induced by exposure to 1 M citric acid aerosol generatedby an ultrasonic nebuliser at a nebulisation rate of 0.6 mL/min for 10minutes. Coughs are counted throughout the 10 minute citric acidexposure and for a further 5 minute post-exposure recovery period.

The mean number of citric acid induced cough responses recorded in thevehicle treated guinea pigs is 27±5 coughs with a mean onset time forfirst cough of 62±7 seconds. The level of response is significantlyreduced to 6±2 coughs in codeine-treated animals and the onset to thefirst cough was significantly extended to 170±28 seconds. Pre-treatmentwith theobromine (10 mg/kg) also caused a significant reduction to thenumber of citric acid induced coughs (14±5), as well as small increaseduration to the onset of the first cough (120±23 seconds). Incombination with peppermint oil (0.3 mg/kg or 1 mg/kg), the inhibitoryeffect of theobromine on the citric acid-induced tussive activity waspotentiated substantially only with the higher dose both in respect tothe total number of coughs (15±3 c.f. 6±2) and the onset time to thefirst cough (115±17 seconds c.f. 130±25 seconds). Peppermint oil on itsown has no effect on total number of coughs (26±10) or on the onset timeto the first cough (75±8 seconds).

Example 11 Theobromine and an ACE Inhibitor

This example illustrates the antitussive activity of theobromine incombination with an ACE inhibitor.

Thirty male Dunkin Hartley guinea pigs (400-500 g, supplied by Harlan UKLtd) are randomly allocated equally into one of five groups. Group 1animals are administered vehicle only; Group 2 animals areintra-peritoneally dosed (volume 2 mL/kg) with 25 mg/kg of codeine;Group 3 animals are orally dosed (volume 2 mL/kg) with 30 mg/kg oftheobromine; Group 4 animals are orally dosed with 30 mg/kg ofcaptopril; and Group 5 animals are orally dosed with 30 mg/kg oftheobromine and 30 mg/kg captopril. Pre-treatments with theobromine andcaptopril are administered 120 minutes prior to citric acid exposure.Pre-treatments with codeine are administered 30 minutes prior to citricacid exposure. Individual guinea pigs are placed in an exposure chamberwith an airflow of 2 L/min for 10 minutes prior to citric acid exposureto allow acclimatisation. Cough responses are induced by exposure to 1 Mcitric acid aerosol generated by an ultrasonic nebuliser at anebulisation rate of 0.6 mL/min for 10 minutes. Coughs are countedthroughout the 10 minute citric acid exposure and for a further 5 minutepost-exposure recovery period.

The mean number of citric acid induced cough responses recorded in thevehicle treated guinea pigs is 29±9 coughs with a mean onset time forfirst cough of 66±8 seconds. The level of response is significantlyreduced to 7±3 coughs in codeine-treated animals and the onset to thefirst cough was significantly extended to 170±28 seconds. Pre-treatmentwith theobromine (30 mg/kg) also caused a significant reduction to thenumber of citric acid induced coughs (10±4), as well as small increaseduration to the onset of the first cough (125±22 seconds). Pretreatmentwith captopril (30 mg/kg), substantially increased the protussive effectof citric acid, with total number of coughs (45±12) and the shortenedthe onset time to the first cough (34±12 seconds). Combining thecaptopril and theobromine reduced the total number of coughs compared tothe captopril alone group (18±10) and lengthened the onset time to thefirst cough (70±12 seconds).

Example 12 Treatment of a Coughing Condition

A 26 year old woman complains of coughing all the time. After routinehistory and physical examination, a physician diagnosis the woman with acoughing condition associated with smoking. The woman is treated byinhalatory administration a pharmaceutical composition comprisingtheobromine and dextromethophan as disclosed herein taken four timesdaily. Alternatively, the woman may be treated by oral administration apharmaceutical composition comprising theobromine and dextromethophan asdisclosed herein taken twice times daily. The patient's condition ismonitored and after about 2 days from treatment, the woman indicates sheis experiencing decreased coughing episodes. At two and four monthcheck-ups, the woman indicates that she is still taking the medicationand is still experiencing decreased episodes of coughing. This decreasein coughing episodes indicates successful treatment with thepharmaceutical composition disclosed herein.

In a similar manner, a pharmaceutical composition comprising theobromineand any of the therapeutic compounds disclosed herein, such as, e.g., anon-opiate antitussive, an opiate antitussive, a decongestant, anexpectorant, a mucolytic agent, an anti-histamine, a NSAID, aneuropathic pain agent, a terpene, or any combination thereof, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 78 year old man complains of coughing all the time. After routinehistory and physical examination, a physician diagnosis the man with acoughing condition associated with tuberculosis. The man is treated byinhalatory administration a pharmaceutical composition comprisingtheobromine and codeine as disclosed herein taken four times daily.Alternatively, the man may be treated by oral administration apharmaceutical composition comprising theobromine and codeine asdisclosed herein taken twice times daily. The patient's condition ismonitored and after about 2 days from treatment, the man indicates he isexperiencing decreased coughing episodes. At two and four monthcheck-ups, the man indicates that he is still taking the medication andis still experiencing decreased episodes of coughing. This decrease incoughing episodes indicates successful treatment with the pharmaceuticalcomposition disclosed herein.

In a similar manner, a pharmaceutical composition comprising theobromineand any of the therapeutic compounds disclosed herein, such as, e.g., anon-opiate antitussive, an opiate antitussive, a decongestant, anexpectorant, a mucolytic agent, an anti-histamine, a NSAID, aneuropathic pain agent, a terpene, or any combination thereof, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 58 year old male complains of coughing due to breathing difficulty.After routine history and physical examination, a physician diagnosisthe man with a coughing condition associated with a chronic obstructivepulmonary disease (COPD). The man is treated by inhalatoryadministration a pharmaceutical composition comprising theobromine andpseudoephidrine as disclosed herein taken four times daily.Alternatively, the man may be treated by oral administration apharmaceutical composition comprising theobromine and pseudoephidrine asdisclosed herein taken twice times daily. The patient's condition ismonitored and after about 2 days from treatment, the man indicates he isexperiencing decreased coughing episodes. At two and four monthcheck-ups, the man indicates that he is still taking the medication andis still experiencing decreased episodes of coughing. This decrease incoughing episodes indicates successful treatment with the pharmaceuticalcomposition disclosed herein.

In a similar manner, a pharmaceutical composition comprising theobromineand any of the therapeutic compounds disclosed herein, such as, e.g., anon-opiate antitussive, an opiate antitussive, a decongestant, anexpectorant, a mucolytic agent, an anti-histamine, a NSAID, aneuropathic pain agent, a terpene, or any combination thereof, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 18 year old woman complains of coughing and stuffed-up nose. Afterroutine history and physical examination, a physician diagnosis thewoman with a coughing condition associated with a respiratory tractinfection. The woman is treated by inhalatory administration apharmaceutical composition comprising theobromine and ibuprofen asdisclosed herein taken four times daily. Alternatively, the woman may betreated by oral administration a pharmaceutical composition comprisingtheobromine and ibuprofen as disclosed herein taken twice times daily.The patient's condition is monitored and after about 2 days fromtreatment, the woman indicates she is experiencing decreased coughingepisodes. At one and two week check-ups, the woman indicates that she isnot coughing and feels great. This decrease in coughing episodesindicates successful treatment with the pharmaceutical compositiondisclosed herein.

In a similar manner, a pharmaceutical composition comprising theobromineand any of the therapeutic compounds disclosed herein, such as, e.g., anon-opiate antitussive, an opiate antitussive, a decongestant, anexpectorant, a mucolytic agent, an anti-histamine, a NSAID, aneuropathic pain agent, a terpene, or any combination thereof, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 47 year old woman complains of coughing and runny nose. After routinehistory and physical examination, a physician diagnosis the woman with acoughing condition associated with an allergy. The woman is treated byinhalatory administration a pharmaceutical composition comprisingtheobromine and chlorpheniramine as disclosed herein taken four timesdaily. Alternatively, the woman may be treated by oral administration apharmaceutical composition comprising theobromine and chlorpheniramineas disclosed herein taken twice times daily. The patient's condition ismonitored and after about 2 days from treatment, the woman indicates sheis experiencing decreased coughing episodes. At one and two monthcheck-ups, the woman indicates that she is not coughing and does nothave a runny nose. This decrease in coughing episodes indicatessuccessful treatment with the pharmaceutical composition disclosedherein.

In a similar manner, a pharmaceutical composition comprising theobromineand any of the therapeutic compounds disclosed herein, such as, e.g., anon-opiate antitussive, an opiate antitussive, a decongestant, anexpectorant, a mucolytic agent, an anti-histamine, a NSAID, aneuropathic pain agent, a terpene, or any combination thereof, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 34 year old male complains of coughing due to breathing difficulty.After routine history and physical examination, a physician diagnosisthe man with a coughing condition associated with a chest cold. The manis treated by inhalatory administration a pharmaceutical compositioncomprising theobromine and guaifenesin as disclosed herein taken fourtimes daily. Alternatively, the man may be treated by oraladministration a pharmaceutical composition comprising theobromine andguaifenesin as disclosed herein taken twice times daily. The patient'scondition is monitored and after about 2 days from treatment, the manindicates he is experiencing decreased coughing episodes. At one and twoweek check-ups, the man indicates that indicates that his chest iscleared and his is not coughing. This decrease in coughing episodesindicates successful treatment with the pharmaceutical compositiondisclosed herein.

In a similar manner, a pharmaceutical composition comprising theobromineand any of the therapeutic compounds disclosed herein, such as, e.g., anon-opiate antitussive, an opiate antitussive, a decongestant, anexpectorant, a mucolytic agent, an anti-histamine, a NSAID, aneuropathic pain agent, a terpene, or any combination thereof, will beformulated into a pharmaceutical composition and administered to thepatient as described above.

A 67 year old male complains of coughing due to a medication includingan ACE inhibitor for hypertension. After routine history and physicalexamination, a physician diagnosis the man with a coughing conditionthat is a side-effect of his ACE inhibitor medication. The man istreated by inhalatory administration a pharmaceutical compositioncomprising theobromine as disclosed herein in conjunction with his ACEinhibitor medication. Alternatively, the man may be treated by oraladministration a pharmaceutical composition comprising theobromine asdisclosed herein in conjunction with his ACE inhibitor medication.Alternatively, the man may be treated by inhalatory administration apharmaceutical composition comprising theobromine and the ACE inhibitoras disclosed herein taken four times daily. Alternatively, the man maybe treated by oral administration a pharmaceutical compositioncomprising theobromine and the ACE inhibitor as disclosed herein takentwice times daily. The patient's condition is monitored and after about2 days from treatment, the man indicates he is experiencing decreasedcoughing episodes. At two and four month check-ups, the man indicatesthat he is still taking the medication and is still experiencingdecreased episodes of coughing. This decrease in coughing episodesindicates successful treatment with the pharmaceutical compositiondisclosed herein.

A 73 year old male complains of coughing due to a medication includingan angiotensin II receptor antagonist for hypertension. After routinehistory and physical examination, a physician diagnosis the man with acoughing condition that is a side-effect of his ACE inhibitormedication. The man is treated by inhalatory administration apharmaceutical composition comprising theobromine as disclosed herein inconjunction with his angiotensin II receptor antagonist medication.Alternatively, the man may be treated by oral administration apharmaceutical composition comprising theobromine as disclosed herein inconjunction with his angiotensin II receptor antagonist medication.Alternatively, the man may be treated by inhalatory administration apharmaceutical composition comprising theobromine and the angiotensin IIreceptor antagonist as disclosed herein taken four times daily.Alternatively, the man may be treated by oral administration apharmaceutical composition comprising theobromine and the angiotensin IIreceptor antagonist as disclosed herein taken twice times daily. Thepatient's condition is monitored and after about 2 days from treatment,the man indicates he is experiencing decreased coughing episodes. At twoand four month check-ups, the man indicates that he is still taking themedication and is still experiencing decreased episodes of coughing.This decrease in coughing episodes indicates successful treatment withthe pharmaceutical composition disclosed herein.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

1. A method of treating a coughing condition, the method comprising thestep of administering a therapeutically-effective amount of an oralpharmaceutical composition to an individual in need thereof, the oralpharmaceutical composition comprising 0.5 mg/mL to 10 mg/mL ofTheobromine, 0.25 mg/mL to 7.5 mg/mL of Diphenhydramine, and 0.1 mg/mLto 5 mg/mL of Phenylephrine, wherein the therapeutically-effectiveamount of the theobromine is at least 60 mg/day and at most 150 mg/day,and wherein administration reduces a symptom associated with thecoughing condition.
 2. The method according to claim 2, wherein the oralpharmaceutical composition comprises 0.5 mg/mL to 6 mg/mL ofTheobromine, 0.5 mg/mL to 5 mg/mL of Diphenhydramine, and 0.1 mg/mL to 3mg/mL of Phenylephrine.
 3. The method according to claim 3, wherein theoral pharmaceutical composition comprises 0.5 mg/mL to 4 mg/mL ofTheobromine, 0.5 mg/mL to 3 mg/mL of Diphenhydramine, and 0.1 mg/mL to 2mg/mL of Phenylephrine.
 4. The method according to claim 4, wherein theoral pharmaceutical composition comprises 1 mg/mL to 3 mg/mL ofTheobromine, 0.5 mg/mL to 2 mg/mL of Diphenhydramine, and 0.1 mg/mL to 1mg/mL of Phenylephrine.
 5. The method according to claim 5, wherein theoral pharmaceutical composition comprises 2 mg/mL of Theobromine, 1.25mg/mL of Diphenhydramine, and 0.5 mg/mL of Phenylephrine.
 6. The methodaccording to claim 1, wherein the therapeutically-effective amount ofthe oral pharmaceutical composition administered to the individualcomprises between 60 mg/day and 150 mg/day of Theobromine, 20 mg/day and100 mg/day of Diphenhydramine, and 5 mg/day and 50 mg/day ofPhenylephrine.
 7. The method according to claim 6, wherein thetherapeutically-effective amount of the oral pharmaceutical compositionadministered to the individual comprises between 60 mg/day and 120mg/day of Theobromine, 37.5 mg/day and 75 mg/day of Diphenhydramine, and15 mg/day and 30 mg/day of Phenylephrine.
 8. The method according toclaim 1, wherein the coughing condition comprises an acute coughingcondition, a subacute coughing condition a chronic coughing condition.9. The method according to claim 1, wherein the coughing conditioncomprises a non-productive coughing condition or a productive coughingcondition.
 10. The method according to claim 1, wherein the coughingcondition comprises a cough associated with a disease or disorder. 11.The method according to claim 10, wherein the disease or disorder is anasthma, an atopic cough, a bronchitis, a gastroesophageal refluxdisease, an infection of the respiratory tract, an inflammation, amedication, a pollutant, a post-nasal drip, a smoking event, a vagalnerve irritation, a diseases of the external auditory canal, a lungdisease, a lung tumor, a habit cough, a tic, a Tourette syndrome, acardiovascular disease, or a post-infectious cough.
 12. The methodaccording to claim 11, wherein the infection of the respiratory tractincludes a cold, croup, pertussis, pneumonia, or tuberculosis.
 13. Themethod according to claim 1, wherein the symptom includes coughing,hoarseness, sore throat, breathing difficulty, respiratory congestion,wheezing, respiratory constriction, respiratory inflammation, musclespasms associated with a cough, phlegm production, fainting, insomnia,vomiting, subconjunctival hemorrhage, cough defecation, cough urination,abdominal hernia, pelvic hernia, costochondritis, lower rib fracture, orany combination thereof.
 14. A method of treating a coughing condition,the method comprising the step of administering atherapeutically-effective amount of an oral pharmaceutical compositionto an individual in need thereof, the oral pharmaceutical compositioncomprising 0.5 mg/mL to 6 mg/mL of Theobromine, 0.25 mg/mL to 4 mg/mL ofDiphenhydramine, and 0.1 mg/mL to 3 mg/mL of Phenylephrine, wherein thetherapeutically-effective amount of the theobromine is at most 250mg/day, and wherein administration reduces a symptom associated with thecoughing condition.
 15. The method according to claim 14, wherein thetherapeutically-effective amount of the oral pharmaceutical compositionadministered to the individual comprises between 60 mg/day and 150mg/day of Theobromine, 20 mg/day and 100 mg/day of Diphenhydramine, and5 mg/day and 50 mg/day of Phenylephrine.
 16. The method according toclaim 15, wherein the therapeutically-effective amount of the oralpharmaceutical composition administered to the individual comprisesbetween 60 mg/day and 120 mg/day of Theobromine, 37.5 mg/day and 75mg/day of Diphenhydramine, and 15 mg/day and 30 mg/day of Phenylephrine.17. A method of treating a coughing condition, the method comprising thestep of administering a therapeutically-effective amount of an oralpharmaceutical composition to an individual in need thereof, thepharmaceutical composition comprising 0.5 mg/mL to 4 mg/mL ofTheobromine, 0.5 mg/mL to 3 mg/mL of Diphenhydramine, and 0.1 mg/mL to 2mg/mL of Phenylephrine, wherein the therapeutically-effective amount ofthe theobromine is at most 250 mg/day, and wherein administrationreduces a symptom associated with the coughing condition.
 18. The methodaccording to claim 17, wherein the oral pharmaceutical compositioncomprises 1 mg/mL to 3 mg/mL of Theobromine, 0.5 mg/mL to 2 mg/mL ofDiphenhydramine, and 0.1 mg/mL to 1 mg/mL of Phenylephrine.
 19. Themethod according to claim 17, wherein the therapeutically-effectiveamount of the oral pharmaceutical composition administered to theindividual comprises between 60 mg/day and 150 mg/day of Theobromine, 20mg/day and 100 mg/day of Diphenhydramine, and 5 mg/day and 50 mg/day ofPhenylephrine.
 20. The method according to claim 19, wherein thetherapeutically-effective amount of the oral pharmaceutical compositionadministered to the individual comprises between 60 mg/day and 120mg/day of Theobromine, 37.5 mg/day and 75 mg/day of Diphenhydramine, and15 mg/day and 30 mg/day of Phenylephrine.